USE OF AGENTS THAT DOWN-REGULATE EXPRESSION OF TANIS AND/OR P21 Waf1/Cip1/Sd1 GENES, AND USE OF AGENTS THAT INHIBIT, DEGRADE, SEQUESTER OR PREVENT THE NEUROTOXICITY OF GENE PRODUCT PROTEINS OF TANIS AND P21 Waf1/Cip1/Sd1 GENES

Abstract

vides compositions and methods for treating glaucoma, ocular hypertension, and age-related macular degeneration. More specifically, the present invention describes the use of agents that down-regulate expression of tanis and/or p21.sup.Waf1/Cip1/Sd1 genes to treat such disorders of the eye.

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001]The present application is a divisional of patent application Ser. No. 11/006,007, filed Dec. 7, 2004, which claims priority from Provisional Application Ser. No. 60/530,436 filed Dec. 17, 2003.

BACKGROUND OF THE INVENTION

[0002]1. Field of the Invention

[0003]The present invention relates to the field of diagnosis and treatment of glaucoma. More specifically, the invention provides methods and compositions for treating ocular hypertension, glaucoma and age-related macular degeneration (ARMD) and for identifying therapeutic agents to treat these blinding diseases.

[0004]2. Description of the Related Art

[0005]There are a number of ocular conditions that are caused by, or aggravated by, damage to the optic nerve head, degeneration of ocular tissues, and/or elevated intraocular pressure. For example, "glaucomas" are a group of debilitating eye diseases that are a leading cause of irreversible blindness in the United States and other developed nations. Primary Open Angle Glaucoma ("POAG") is the most common form of glaucoma. The disease is characterized by the degeneration of the trabecular meshwork, leading to obstruction of the normal ability of aqueous humor to leave the eye without closure of the space (e.g., the "angle") between the iris and cornea (Vaughan, D. et al., (1992)). A characteristic of such obstruction in this disease is an increased intraocular pressure ("IOP"), resulting in progressive visual loss and blindness if not treated appropriately and in a timely fashion. The disease is estimated to affect between 0.4% and 3.3% of all adults over 40 years old (Leske, M. C. et al. (1986); Bengtsson, B. (1989); Strong, N. P. (1992)). Moreover, the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N. P., (1992)).

[0006]Glaucoma affects three separate tissues in the eye. The elevated IOP associated with POAG is due to morphological and biochemical changes in the trabecular meshwork (TM), a tissue located at the angle between the cornea and iris. Most of the nutritive aqueous humor exits the anterior segment of the eye through the TM. The progressive loss of TM cells and the build-up of extracellular debris in the TM of glaucomatous eyes leads to increased resistance to aqueous outflow, thereby raising IOP. Elevated IOP, as well as other factors such as ischemia, cause degenerative changes in the optic nerve head (ONH) leading to progressive "cupping" of the ONH and loss of retinal ganglion cells and axons. The detailed molecular mechanisms responsible for glaucomatous damage to the TM, ONH, and the retinal ganglion cells are unknown.

[0007]Twenty years ago, the interplay of ocular hypertension, ischemia and mechanical distortion of the optic nerve head were heavily debated as the major factors causing progression of visual field loss in glaucoma. Since then, other factors including excitotoxicity, nitric oxide, absence of vital neurotrophic factors, abnormal glial/neuronal interplay and genetics have been implicated in the degenerative disease process. The consideration of molecular genetics deserves some discussion insofar as it may ultimately define the mechanism of cell death, and provide for discrimination of the various forms of glaucoma. Within the past 8 years, over 15 different glaucoma genes have been mapped and 7 glaucoma genes identified. This includes six mapped genes (GLC1A-GLC1F) and two identified genes (MYOC and OPTN) for primary open angle glaucoma, two mapped genes (GLC3A-GLC3B) and one identified gene for congenital glaucoma (CYP1B1), two mapped genes for pigmentary dispersion/pigmentary glaucoma, and a number of genes for developmental or syndromic forms of glaucoma (FOXC1, PITX2, LMX1B, PAX6).

[0008]Thus, each form of glaucoma may have a unique pathology and accordingly a different therapeutic approach to the management of the disease may be required. For example, a drug that effects the expression of enzymes that degrade the extracellular matrix of the optic nerve head would not likely prevent RGC death caused by excitotoxicity or neurotrophic factor deficit. In glaucoma, RGC death occurs by a process called apoptosis (programmed cell death). It has been speculated that different types of insults that can cause death may do so by converging on a few common pathways. Targeting downstream at a common pathway is a strategy that may broaden the utility of a drug and increase the probability that it may have utility in the management of different forms of the disease. However, drugs that effect multiple metabolic pathways are more likely to produce undesirable side-effects. With the advent of gene-based diagnostic kits to identify specific forms of glaucoma, selective neuroprotective agents can be tested with the aim of reducing the degree of variation about the measured response.

[0009]Glaucoma is currently diagnosed based on specific signs of the disease (characteristic optic nerve head changes and visual field loss). However, over half of the population with glaucoma are unaware they have this blinding disease and by the time they are diagnosed, they already have irreversibly lost approximately 30-50% of their retinal ganglion cells. Thus, improved methods for early diagnosis of glaucoma are needed.

[0010]Current glaucoma therapy is directed to lowering IOP, a major risk factor for the development and progression of glaucoma. However, none of the current IOP lowering therapies actually intervenes in the glaucomatous disease process responsible for elevated IOP and progressive damage to the anterior segment continues. This is one possible reason why most patients become "resistant" to conventional glaucoma therapies. Thus, what is needed is a therapeutic method for altering (by inhibiting or even reversing) the disease process.

[0011]Another blinding disease is age-related macular degeneration (ARMD) that affects the outer retina, retinal pigmented epithelial cells, Bruch's membrane, and the choroid. (Ambati et al. 2003). The hallmarks of this disease are diffuse and focal thickening of the Bruch's membrane due to deposition of lipoproteins (drusen) leading to retinal dysfunction culminating in retinal detachment and loss of vision. Other lipoproteins, such as Tanis gene receptor and SAA, may also be deposited at the Bruch's membrane to exacerbate the pathology and retinal dysfunction.

[0012]There are several reports suggesting that primary amyloidosis may be associated with glaucoma. For example, it was found that amyloid was deposited in various ocular tissues including the vitreous, retina, choroid, iris, lens, and trabecular meshwork in primary systemic amyloidosis patients (Schwartz et al. 1982). Ermilov et al. (1993) reported that in 478 eyes of 313 patients (aged 25 years to 90 years) with cataracts, glaucoma, and/or diabetes mellitus, 66 (14%) of the eyes contained amyloid-pseudoexfoliative amyloid (PEA) proteins. Krasnov et al. (1996) reported that 44.4% of 115 patients with open-angle glaucoma revealed extracellular depositions of amyloid proteins. Finally, amyloidosis was revealed in the sclera in 82% of the cases and in the iris in 70% of the cases. A number of clinical conditions, including Alzheimer's disease, exhibit abnormal amyloid deposits in tissues associated with the disease. However, amyloids are molecularly heterogeneous and encoded by different amyloid genes. The previous reports are unclear regarding which amyloid(s) might be associated with glaucoma.

[0013]To date, more than 100 genes have been mapped or cloned that may be associated with retinal degeneration. The pathogenesis of retinal degenerative diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) is multifaceted and can be triggered by environmental factors in those who are genetically predisposed. One such environmental factor, light exposure, has been identified as a contributing factor to the progression of retinal degenerative disorders such as ARMD (Young 1988). Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium (RPE) of the outer retina (Noell et al. 1966; Bressler et al. 1988; Curcio et al. 1996); they share a common mechanism of cell death, apoptosis (Ge-Zhi, et al. 1996; Abler et al. 1996); light has been implicated as an environmental risk factor for progression of ARMD and RP (Taylor et al. 1992; Naash et al. 1996); and therapeutic interventions which inhibit photo-oxidative injury have also been shown to be effective in animal models of neurodegenerative retinal disease (LaVail et al. 1992; Fakforovich et al. 1990).

[0014]To date, there are no approved effective therapies for the treatment of ocular neovascular diseases which do not include the destruction of healthy viable tissue. There are certainly no therapies specifically directed at eliminating or inhibiting the deposition and accumulation of amyloid proteins, drusen or amyloid-like proteins including SAA on the Bruch's membrane in the retina as in ARMD. Such accumulation of amyloid and/or drusen and other lipoproteins including SAA causes retinal dysfunction by several mechanisms including disruption of retinal pigmented epithelial (RPE) cell function due to thickening of Bruch's membrane, and RPE detachment resulting in rapid loss of visual acuity followed by macular atrophy and retinal detachment (Ciulla et al. 1998). Additionally, the deposited drusen and/or amyloid proteins including SAA could exert direct neurotoxic effects on the RPE cells and neighboring cells in the retina akin to the well known toxic effects of such amyloid proteins and amyloid/lipid complexes observed in brain cell death as in Alzheimer's disease (Lambert et al. 1998; Liu and Schubert 1997; Pike et al. 1993; Nakagami et al. 2002) in retina (Jen et al. 1998). Although panretinal photocoagulation is the current medical practice for the treatment of diabetic retinopathy and ARMD and is effective in inhibiting retinal neovascularization, this procedure destroys healthy peripheral retinal tissue. This destruction of healthy tissue decreases the retinal metabolic demand and thereby reduces retinal ischemia driven neovascularization. Photodynamic therapy (PDT) is a procedure in which a photoactivatable dye is given systemically followed by laser activation of the dye in the eye at the site of new blood vessel formation (Asrani & Zeimer 1995; Asrani et al. 1997; Husain et al. 1997; Lin et al. 1994). The photoactivated drug generates free oxygen radicals which seal the newly formed blood vessels and thereby prevent or reduce their growth, at least temporarily. This procedure has been used in patients with the exudative form of macular degeneration and many patients show regression of their subretinal neovascular membranes. Unfortunately, it appears that the PDT-induced inhibition of retinal neovascularization is risky, expensive and provides transient and temporary relief lasting only 6-12 weeks (Gragoudas et al. 1997; Sickenberg et al. 1997; Thomas et al. 1998).

[0015]Thus, there is an urgent need for therapeutic methods for altering (by inhibiting or even reversing) the disease processes of glaucoma and ARMD.

SUMMARY OF THE INVENTION

[0016]The present invention overcomes these and other drawbacks of the prior art by providing methods to diagnose and compositions to treat ocular hypertension, glaucoma and ARMD. The present invention overcomes these and other drawbacks of the prior art by providing compositions and methods for treating ARMD by sequestering and/or degrading Tanis gene product protein (TGPP) and/or p21.sup.Waf1/Cop1/Sdi1 gene product protein (p21GPP) in ocular tissues at the back of the eye, specifically at the Bruch's membrane, outer retina, macula and sub-retinal space. In addition, compositions and methods to prevent the generation of TGPP and/or p21 GPP and/or to prevent the neurotoxic effects of such gene product proteins are provided to treat ARMD. In one aspect, the present invention provides a method for treating ARMD by administering to a patient in need thereof a therapeutically effective amount of a composition comprising an agent that sequesters TGPP or p21 GPP in ocular tissue and/or an agent that degrades TGPP or p21 GPP in ocular tissue. Such sequestration and/or degradation modulates the expression of the TGPP and p21 GPP, such that the patient's condition is treated. In addition, agents that stop or reduce the initial activation of Tanis and p21.sup.Waf1/Cop1/Sdi1 genes and/or prevent nerve cell death due to the presence of TGPP or p21 GPP would also be useful to treat the patient's ARMD condition. In preferred embodiments, the agent will be a small molecular weight molecule, antibody, protein, peptide, peptidomimetic, or nucleic acid.

[0017]Preferably, the agents for use in the compositions and methods of the present invention will mainly be chosen from the following:

[0018]Compounds that may be useful for preventing the production of TGPP or p21 GPP would include: γ-secretase inhibitors such as talsaclidine (Hock et al. 2003), Xanomeline, L-689660, L-685458, McN-A-343, CDD-0097, fenchylamine, MG132, WPE-111-31C, MW-11-36C/26A, MW-167, CM-265, lactacystin, DNPS1 and DAPT (Lanz et al. 2003). Other compounds of use may include the statin family, e.g. pravastatin, atorvastatin (see Burns and Duff 2003) and presenilinase inhibitors such as pepstatin A (Xia 2003) and talsaclidine (Hock et al. 2003).

[0019]Compounds that may be useful for promoting degradation of TGPP or p21 GPP may include glycoaminoglycans and congo red (J. Neurochem. 70: 292-298 [1998]).

[0020]Compounds that may be useful for promoting sequestration or clearance of TGPP or p21GPP may include gelsolin and ganglioside GM1 (Matsuoka et al. 2003). In addition, antibodies raised against drusen, and/or amyloid proteins and/or against amyloid-like proteins would be useful for sequestration and clearance of the former detrimental proteins as has been shown in the brain (Schenk et al. 1999; Janus et al. 2000; Morgan et al. 2000).

[0021]Compounds that may be useful for preventing or diminishing the neurotoxic effects of TGPP or p21GPP include RS-0466 (Nakagami et al. 2002c; Nakagami et al. 2002b), V-type ATPase inhibitors (bafilomycin and concanamycin; Kane et al. 1999), tachykinin peptides and their non-peptide analogs (Yankner et al. 1990), α-lipoic acid (Zhang et al. 2001), propentofylline (Koriyama et al. 2003), glycogen synthase kinase-3β (GSK-3β) inhibitors (Eldar-Finkelman 2002; Caricasole et al. 2003), memantine (Frankiewicz and Parsons 1999), mixed cyclin-dependent kinase-GSK3β inhibitors (Damiens et al. 2001), COX-2 inhibitors (Xiang et al. 2002) and propentofylline (Koriyama et al. 2003).

[0022]The present invention further provides a method of treating glaucoma by administering a composition containing a p21.sup.Waf1/Cip/Sdi1 gene product protein (see below) inhibitor and/or inhibitors of CDK1, CDK2, CDK5 and CDK9, and inhibitors of cJAK and ASRK-1 including the following agents: olomoucine, roscovitine, purvalanol, kenpaullone, alsterpaullone, indirubins, flavopiridol, stauroporine and analogs and derivatives of the above compounds.

[0023]In one aspect, the present invention provides a method for treating glaucoma by administering to a patient in need thereof a therapeutically effective amount of a composition comprising an agent that interacts with a gene encoding a serum amyloid A (SAA) receptor (SEQ ID NO:12), wherein said interaction decreases the expression of SAA (SEQ ID NO:1).

[0024]In another aspect, the present invention provides a method for treating glaucoma by administering to a patient in need thereof a therapeutically effective amount of a composition comprising a Tanis antagonist.

[0025]In preferred aspects, the agent for use in the methods of the invention is a peroxisome proliferator-activated receptor α (PPARα) agonist, tachykinin peptide or non-peptide analogs thereof, or α-lipoic acid. More preferably, the agent is fenofibrate, Wy-14643, (4-chloro-6-(2,3-xylidino)-2-pryrimidinylthiol)-acetic acid), ciprofibrate, 2-bromohexadecanoic acid, bezafibrate and ciglitizone, bafilomycin or concanamycin.

[0026]In yet another aspect, the invention provides a method for treating glaucoma by administering to a patient in need thereof a therapeutically effective amount of a composition comprising a p21 antagonist.

[0027]The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a Tanis antagonist and a pharmaceutical carrier.

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

[0028]Glaucoma is a heterogeneous group of optic neuropathies that share certain clinical features. The loss of vision in glaucoma is due to the selective death of retinal ganglion cells in the neural retina that is clinically diagnosed by characteristic changes in the visual field, nerve fiber layer defects, and a progressive cupping of the ONH. One of the main risk factors for the development of glaucoma is the presence of ocular hypertension (elevated intraocular pressure, IOP). IOP also appears to be involved in the pathogenesis of normal tension glaucoma where patients have what is often considered to be normal IOP. The elevated IOP associated with glaucoma is due to elevated aqueous humor outflow resistance in the trabecular meshwork (TM), a small specialized tissue located in the iris-corneal angle of the ocular anterior chamber. Glaucomatous changes to the TM include a loss in TM cells and the deposition and accumulation of extracellular debris including proteinaceous plaque-like material. In addition, there are also changes that occur in the glaucomatous optic nerve head (ONH). In glaucomatous eyes, there are morphological and mobility changes in ONH glial cells. In response to elevated IOP and/or transient ischemic insults, there is a change in the composition of the ONH extracellular matrix and alterations in the glial cell and retinal ganglion cell axon morphologies.

[0029]It has been found that the expression of Serum Amyloid A (SAA) mRNA is significantly upregulated in glaucomatous TM tissues and cells. The differential expression seen has been verified using Affymetrix gene chips by real time quantitative polymerase chain reaction (QPCR). This is the first time SAA has been shown to be expressed in the TM (U.S. application Ser. No. 60/530,430).

[0030]Human SAA comprises a number of small, differentially expressed apolipoproteins encoded by genes localized on the short arm of chromosome 11. There are four isoforms of SAAs. SAM (SEQ ID NO:2), encoded by SEQ ID NO:1, and SAA2 (SEQ ID NO:4), encoded by SEQ ID NO:3, are known as acute phase reactants, like C-reactive protein, that is, they are dramatically upregulated by proinflammatory cytokines. The 5'UTR promoter regions of SAM and SAA2 genes are also provided (SEQ ID NO:12 and SEQ ID NO:13, respectively). SAA3 (SEQ ID NO:5) is a pseudogene and SAA4 (SEQ ID NO:6) is a low level endogenously expressed gene encoding endogenous SAA4 (SEQ ID NO:7). SAA2 has two isoforms, SAA2α (SEQ ID NO:9), encoded by SEQ ID NO:8, and SAA2β (SEQ ID NO:11), encoded by SEQ ID NO:10, which differ by only one amino acid. SAA1 and SAA2 proteins are 93.5% identical at the amino acid level (SEQ ID NO:2 and SEQ ID NO:4, respectively) and these genes are 96.7% identical at the nucleotide level (SEQ ID NO:1 and SEQ ID NO:3, respectively).

[0031]SAA functions as an apolipoprotein and is expressed in a number of tissues in addition to the liver (Miida et al. 1999). However, over-expression of SAM or SAA2 leads to the formation of linear fibrils in amyloid deposits, which can lead to pathogenesis and thus many types of diseases (Uhlar and Whitehead 1999; Liang et al. 1997). SAA plays an important role in infections, inflammation, and in the stimulation of tissue repair. SAA concentration may increase up to 1000-fold following inflammation, infection, necrosis, and decline rapidly following recovery. Thus, serum SAA concentration is considered to be a useful marker with which to monitor inflammatory disease activity. Hepatic biosynthesis of SAA is up-regulated by pro-inflammatory cytokines, leading to an acute phase response. Chronically elevated SAA concentrations are a prerequisite for the pathogenesis of secondary amyloidosis, a progressive and sometimes fatal disease characterized by the deposition in major organs of insoluble plaques composed principally of proteolytically cleaved SAA. This same process also may lead to atherosclerosis. There is a requirement for both positive and negative SAA control mechanisms to maintain homeostasis. These mechanisms permit the rapid induction of SAA expression to fulfill host-protective functions, but they also must ensure that SAA expression is rapidly returned to baseline levels to prevent amyloidosis. These mechanisms include modulation of promoter activity involving, for example, the inducer nuclear factor kB (NF-kB) and its inhibitor IkB, up-regulation of transcription factors of the nuclear factor for interleukin-6 (NF-IL6) family, and transcriptional repressors such as yin and yang 1 (YY1). Post-transcriptional modulation involving changes in mRNA stability and translation efficiency permit further up- and down-regulatory control of SAA protein synthesis to be achieved. In the later stages of the AP response, SAA expression is effectively down-regulated via the increased production of cytokine antagonists such as the interleukin-1 receptor antagonist (IL-1Ra) and of soluble cytokine receptors, resulting in less signal transduction driven by pro-inflammatory cytokines (Jensen and Whitehead, 1998).

[0032]There are several reports suggesting that primary amyloidosis may be associated with glaucoma. For example, it was found that amyloid was deposited in various ocular tissues including the vitreous, retina, choroid, iris, lens, and TM in primary systemic amyloidosis patients (Schwartz et al. 1982). Ermilov et al. (1993) reported that in 478 eyes of 313 patients, aged 25 years to 90 years, with cataracts, glaucoma, and/or diabetes mellitus, 66 (14%) of the eyes contained amyloid-pseudoexfoliative amyloid (PEA). Krasnov et al. (1996) reported that 44.4% of 115 patients with open-angle glaucoma revealed extracellular depositions of amyloid. Amyloidosis was revealed in the sclera in 82% of the cases and in the iris in 70% of the cases. A number of clinical conditions, including Alzheimer's disease, exhibit aberrant amyloid tissue deposits associated with disease. However, amyloids are molecularly heterogeneous and encoded by different amyloid genes. The previous reports are unclear regarding which amyloid(s) are associated with glaucoma.

[0033]SAA gene expression is elevated significantly in glaucomatous TM tissues. Increased SAA may be involved in the generation of elevated IOP and damage to the optic nerve leading to vision loss in glaucoma patients.

[0034]The Tanis gene (SEQ ID NO:14) is a recently identified gene that encodes a membrane protein (SEQ ID NO:15) said to bind to SAA (Walder et al. 2002). It is believed that therapeutic intervention of the interaction between SAA and its putative receptor, encoded by the Tanis gene, may modulate SAA expression levels and/or receptor-mediated SAA signaling. Methods for the identification of agents that interfere with this interaction and their use for the treatment of ocular hypertension, glaucoma and ARMD are also provided herein.

[0035]It has also recently been discovered that a gene called p21.sup.Waf1/Cip/Sdi1 (SEQ ID NO:16) activates SAA and activates the gene APP that produces amyloid protein which forms plaques in the brain that are hallmarks of Alzheimer's disease (Chang et at 2000; Kindy et al. 1999; Johan et al. 1997). In addition, p21.sup.Waf1/Cip/Sdi1-induced gene expression results in over production of extracellular matrix (ECM) proteins including fibronectin-1, plaminogen activator inhibitor, tissue-type plasminogen activator, integrin β3 (Chang et al. 2000) which may be contributive factors in the glaucomatous situation. Likewise, p21.sup.Waf1/Cip/Sdi1-induced connective tissue growth factor and galectin-3 (Chang et al. 2000) may also play significant roles in deposition of ECM proteins and other components of ECM in the anterior eye segment leading to ocular hypertension and glaucoma. Therefore, it is believed that inhibition of p21.sup.Waf1/Cip/Sdi1 gene would be useful in the treatment of the pathophysiology of glaucoma. Interestingly, since p21.sup.Waf1/Cip/Sdi1 gene expression results in natural inhibition of cyclin-dependent kinases (CDK) (Chang et al. 2000), and since p21.sup.Waf1/Cip/Sdi1 was reported to bind c-Jun amino-terminal kinase (cJAK), apoptosis-signal-regulating kinase 1 (ASRK-1) and Gadd45 (Chang et al. 2000), it follows that inhibitors of these kinases would also act as p21.sup.Waf1/Cip/Sdi1 antagonists. Accordingly, inhibitors of CDK1, 2, 5 and 9, and inhibitors of cJAK and ASRK-1 would be useful for treating ocular hypertension, glaucoma and ARMD. Agents which may modulate the interaction of SAA and its putative receptor and the TGPP or p21GPP include, but are not limited to, peroxisome proliferator-activated receptor α (PPARα) agonists, tachykinin peptides and their non-peptide analogs, and α-lipoic acid. PPARα agonists include arachidonic acid, linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, 8(S)-HETE, (±)ibuprofin, indomethacin, leukotriene B₄, meclofenamate, prostaglandin A₁, prostaglandin A₂, prostaglandin D₁, prostaglandin D₂, prostaglandin J₂, 15-deoxy-Δ¹²-prostaglandin J₂, WY 14643, ciglitizone, carbaprostacyclin and prostacyclin. Examples of preferred agents for use in the present invention include fenofibrate, WY 14643, (4-chloro-6-(2,3-xylidino)-2-pryrimidinylthiol)-acetic acid), ciprofibrate, 2-bromohexadecanoic acid, bezafibrate, ciglitizone, bafilomycin, and concanamycin.

[0036]In another aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a Tanis gene product protein inhibitor and/or Tani gene inhibitor or a p21.sup.Waf1/Cip/Sdi1 gene inhibitor or p21.sup.Waf1/Cip/Sdi1 gene product protein inhibitor and a pharmaceutical carrier.

[0037]The Compounds of this invention, can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The Compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye. The Compounds may be combined with opthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a Compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an opthalmologically acceptable surfactant to assist in dissolving the Compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the Compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.

[0038]The Compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8. The establishment of a specific dosage regimen for each individual is left to the discretion of the clinicians. The Compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0% by weight. The dosage form may be a solution, suspension microemulsion. Thus, for topical presentation 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.

[0039]The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Formulation of Tanis Gene (TG) Inhibitor or TG Product Protein Inhibitor or p21.sup.Waf1/Cip/Sdi1 Gene Inhibitor or Inhibitor of p21.sup.Waf1/Cip/Sdi1 Gene Product Protein for Topical Ocular Application

[0040]1% suspension or solution of Tanis gene inhibitor (TGI) or inhibitor of Tanis gene product protein (TGPPI) or p21.sup.Waf1/Cip/Sdi1 gene inhibitor (p21GI) or inhibitor of p21G product protein (p21GPPI) for topical ocular application:

TABLE-US-00001 Description Conc. Units Purpose TGI or TGPPI or p21GI or 1% W/V % active ingredient p21GPPI hydroxypropyl 0.5% W/V % viscosity modifier methylcellulose (2910) (E4M), USP dibasic sodium phosphate 0.2% W/V % buffering agent (anhydrous), usp sodium chloride, usp 0.75% W/V % tonicity agent disodium edta 0.01% W/V % chelating agent (edetate disodium), usp polysorbate 80, nf 0.05% W/V % wetting agent benzalkonium chloride, nf 0.01% W/V % preservative sodium hydroxide, nf q.s. pH W/V % pH adjust hydrochloric acid, nf q.s. pH W/V % pH adjust purified water, usp q.s. 100% W/V % vehicle

[0041]In similar other examples, TGI or TGPPI or p21GI or p21GPPI will be substituted by agents that sequester or degrade the above or agents that prevent the toxic effects of the above.

[0042]Methods to measure the potency or efficacy of agents that can inhibit the secretion of SAA from cultured cells involve the use of an enzyme-linked immunosorbant assay (ELISA) for human SAA as described by Yamada et al. (2000) and using human peripheral monocytes and monocytic leukaemic cell-line THP-1. In addition, methods to determine the potency and efficacy of agents to inhibit gene expression of p21.sup.Waf1/Cip/Sdi1 can be studies using standard methods described by Chang et al. (2000).

[0043]All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

REFERENCES

[0044]The following references, and the bibliography cited within these, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

PUBLICATIONS

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S. et al., Alzheimer's peptide kills cells of retina in vivo, NATURE 392:140-141 (1998). [0063]Jensen L E and Whitehead A S, BIOCHEM. J. 334:489-503 (1998). [0064]Johan, K. et al., Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils, PROC. NAT. ACAD. SCI USA 95:2558-268 (1997). [0065]Kane, M. D. et al., Inhibitors of V-type ATPases, bafilomycin A1 and concanamycin A, protect against β-amyloid-mediated effects on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, J. NEUROCHEM. 72:1939-1947 (1999). [0066]Kindy, M. S et al., Apolipoprotein serum amyloid A in Alzheimer's disease, J. ALZHEIMER'S DISEASE 1:155-167 (1999). [0067]Koriyama, Y. et al., Propentofylline protects β-amyloid protein-induced apoptosis in cultured rat hippocampal neurons EUR. J. PHARMACOL. 458:235-241 (2003). [0068]Kumon, Y., Hosokawa, T., Suchiro, T., Ideda, Y., Sipe, J. D., and Hashimoto, K., Acute-phase, but not constitutive serum amyloid A (SAA) is chemotactic for cultured human aortic smooth muscle cells, AMYLOID 9:237-241 (2002a). [0069]Kumon, Y., Suchiro, T., Faulkes, D. J., Hosakawa, T., Ideda, Y., Woo, P., Sipe, J. D., and Hashimoto, K., Transcriptional regulation of Serum Amyloid A1 gene expression in human aortic smooth muscle cells involves CCAAT/enhancer binding proteins (C/EBP) and is distinct from HepG2 cells, SCAND. J. IMMUNOL. 56:504-511 (2002b). [0070]Kumon, Y., Suchiro, T., Hashimoto, K., and Sipe, J. D., Dexamethasone, but not IL-1 alone, upregulates acute-phase serum amyloid A gene expression and production by cultured human aortic smooth muscle cells, SCANS J. IMMUNOL. 53:7-12 (2001). [0071]Lambert, M. P. et al., Diffusible, nonfibrillar ligands derived form Aβ_1-42 are potent central nervous system neurotoxins, PROC. NAT. ACAD. SCI. USA 95:6448-6453 (1998). [0072]Lanz, T. A. et al., The γ-secretase inhibitor N--(N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice J. PHARMACOL EXPT. THER. 305:864-871 (2003). [0073]LaVail et al., PROC. NAT'L ACAD. SCI. 89:11249-11253 (1992). [0074]Liang, J. S., Sloane, J. A., Wells, J. M., Abraham, C. R., Fine, R. E., and Sipe, J. D., Evidence for local production of acute phase response apolipoprotein serum amyloid A in Alzheimer's disease brain, NEUROSCI. LETT. 225:73-76 (1997). [0075]Lin et al., CURR. EYE RES. 13(7):513-522 (1994). [0076]Liu, Y and Schubert, D., Cytotoxic amyloid peptides inhibit cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction by enhancing MTT formazan exocytosis, J. NEUROCHEM. 69:2285-2293 (1997). [0077]Marks, N. and Berg, M. J., APP processing enzymes (secretases) as therapeutic targets: insights from the use of transgenics (Tgs) and transfected cells, NEUROCHEM. RES. 28:1049-1062 (2003). [0078]Matsuoka, Y. et al., Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity for β-amyloid, J. NEUROSCI. 23:29-33 (2003). [0079]Miida T., Yamada, T., Yamadera, T., Ozaki, K., Inano, K., Okada, M., Serum amyloid A protein generates pre-beta 1 high-density lipoprotein from alpha-migrating high-density lipoprotein, BIOCHEM. 38(51):16958-16962 (1999). [0080]Morgan, D et al., Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, NATURE 408:982-985 (2000). [0081]Naash et al., INV. OPHTHALM. VIS. SCI. 37:775-782 (1996). [0082]Nakagami, Y and Oda, T., Glutamate exacerbates amyloid β1-42-induced impairment of long-term potentiation in rat hippocampal slices, JPN. J. PHARMACOL. 88:223-226 (2002a). 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S., Differential glucocorticoid enhancement of the cytokine-driven transcriptional activation of the human actue phase serum amyloid A genes, SAA1 and SAA, J. IJ MMUNOL. 169:399-406 (2002). [0092]Uhlar, C. M., and Whitehead, A. S., Serum amyloid A, the major vertebrate acute-phase reactant, EUR. J. BIOCHEM. 265:501-523 (1999). [0093]Urieli-Shoval, S., Cohen, P., Eisenberg, S., and Matzner, Y., Widespread expression of serum amyloid A in histologically normal human tissue. Predominant localization to the epithelium, J. HISTOCHEM. CYTOCHEM. 46:1377-1384 (1998). [0094]Walder et al., Tanis: A link between type 2 diabetes and inflammation? DIABETES 51:1859-1866 (2002). [0095]Xia, W., Relationship between presenilinase and γ-secretase, DRUG NEWS PERSPECT. 16:69-73 (2003). [0096]Yamada et al., Serum amyloid A secretion from monocytic leukaemia cell line THP-1 and cultured human peripheral monocytes, SCAND. J. IMMUNOL. 52:7-12 (2000). [0097]Yamazaki et al., BIOCHEMICAL AND BIOPHYSICAL RES. COMM., 290:1114-1122 (2002). [0098]Young, SUR. OPHTHALM. 32:252-269 (1988). [0099]Zhang, L. et al., α-Lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signaling pathway, NEUROSCI. LETT. 312:125-128 (2001).

Sequence CWU 1

171369DNAhomo sapiens 1atgaagcttc tcacgggcct ggttttctgc tccttggtcc tgggtgtcag cagccgaagc 60ttcttttcgt tccttggcga ggcttttgat ggggctcggg acatgtggag agcctactct 120gacatgagag aagccaatta catcggctca gacaaatact tccatgctcg ggggaactat 180gatgctgcca aaaggggacc tgggggtgtc tgggctgcag aagcgatcag cgatgccaga 240gagaatatcc agagattctt tggccatggt gcggaggact cgctggctga tcaggctgcc 300aatgaatggg gcaggagtgg caaagacccc aatcacttcc gacctgctgg cctgcctgag 360aaatactga 3692122PRThomo sapiens 2Met Lys Leu Leu Thr Gly Leu Val Phe Cys Ser Leu Val Leu Gly Val1 5 10 15Ser Ser Arg Ser Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala 20 25 30Arg Asp Met Trp Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile 35 40 45Gly Ser Asp Lys Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys 50 55 60Arg Gly Pro Gly Gly Val Trp Ala Ala Glu Ala Ile Ser Asp Ala Arg65 70 75 80Glu Asn Ile Gln Arg Phe Phe Gly His Gly Ala Glu Asp Ser Leu Ala 85 90 95Asp Gln Ala Ala Asn Glu Trp Gly Arg Ser Gly Lys Asp Pro Asn His 100 105 110Phe Arg Pro Ala Gly Leu Pro Glu Lys Tyr 115 1203570DNAhomo sapiens 3agggacccgc agctcagcta cagcacagat cagcaccatg aagcttctca cgggcctggt 60tttctgctcc ttggtcctga gtgtcagcag ccgaagcttc ttttcgttcc ttggcgaggc 120ttttgatggg gctcgggaca tgtggagagc ctactctgac atgagagaag ccaattacat 180cggctcagac aaatacttcc atgctcgggg gaactatgat gctgccaaaa ggggacctgg 240gggtgcctgg gccgcagaag tgatcagcaa tgccagagag aatatccaga gactcacagg 300ccatggtgcg gaggactcgc tggccgatca ggctgccaat aaatggggca ggagtggcag 360agaccccaat cacttccgac ctgctggcct gcctgagaaa tactgagctt cctcttcact 420ctgctctcag gagacctggc tatgaggccc tcggggcagg gatacaaagt tagtgaggtc 480tatgtccaga gaagctgaga tatggcatat aataggcatc taataaatgc ttaagaggtc 540aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 5704122PRThomo sapiens 4Met Lys Leu Leu Thr Gly Leu Val Phe Cys Ser Leu Val Leu Ser Val1 5 10 15Ser Ser Arg Ser Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala 20 25 30Arg Asp Met Trp Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile 35 40 45Gly Ser Asp Lys Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys 50 55 60Arg Gly Pro Gly Gly Ala Trp Ala Ala Glu Val Ile Ser Asn Ala Arg65 70 75 80Glu Asn Ile Gln Arg Leu Thr Gly His Gly Ala Glu Asp Ser Leu Ala 85 90 95Asp Gln Ala Ala Asn Lys Trp Gly Arg Ser Gly Arg Asp Pro Asn His 100 105 110Phe Arg Pro Ala Gly Leu Pro Glu Lys Tyr 115 12054286DNAhomo sapiens 5gatggttgac aactcccctc ctcttccccc tcttctactg tctactcctg ggaccaagtg 60agccacgcca gctcagatac tacactgacc acagggaatc ccaccttttc caaggaatgg 120aagttgtgta gggaatattc aaatgttgct tagcattgcc ttagataaga accaaaggga 180cagggaaatc ctctgacagc tatctgcctt ataactttca ttttactgtg cctaaaatat 240gctcagaacc cagaaagagg cataattcct aattttggca ggctctaatc taaaataatg 300attctcaaac atggtgtgac ttttgtctat ttgctttatc ctgggtcact gctcctcttc 360tgtcagatac tgggattcca atgagacaaa tggaaatgga gacgtagacc ctctgacctt 420ctatctttta tctatacaca tacacctgtg tgtgtgtgtg tgtgtgtgtg tgtgcgtgtg 480taaaaccgag tgggtttttt tcttggaatg aaagaatgga ctaacattac aaaaaataaa 540aacttgaaac agaatgtgta ttatccttgg ttgtgtttcc ttggccctgc agcaggatga 600agctctccac tggcatcatt ttctgctccc tggtcctggg tgtcagcagc caaggatggt 660taacattcct caaggcagct ggccaaggtg aggtccacag gatagggggc aggaggctgc 720ttctggctgc ccccaggatg cagctgagca gaggccacat ccccactggg caaaggtgct 780agtgatgcca cagatggata gagaaggggc atggtttttc ataagcgtgg ttcctcatgc 840ttttctggac agctttgaca ctcttctatg aggatcctcc agccgaggtc gcataaggtg 900tgagctgcct cttttcagca ggaccatgag agagatgtgg agttgagggg tgcatgttcc 960cataataccg gtggggctct actgccccct agtgggaaat ctgggacagt tcatgtctat 1020gtctcctggg aagccaggaa gcaggtggat caaaagtgtg aggcgagtcc atggggaagc 1080tgaacggagc caaccgtccc cataaaaaca accaagctta gctgagattt taatacgtac 1140taggcactgt ttaaatgtac taatgaattg gtttccatca tttagtccta tgatgcaagc 1200agcattatcc cttaacagag aagctaacac acacacacac acacacacac taacacacac 1260acacacacac acacacacac aaaccccaag atacgtaaag aagttccaaa gcagagcagg 1320attaacccag gcagtcttgc tctgcagaac ttgctcttaa tcaaggtact ctgctgcttt 1380caaaacaaga gtttcggatt tgtgaacaca tagctcatcc tttatctaag aaatggcaaa 1440taggatgtgg tgcctttgga aggtaagtct agctccactt atcccagtaa aacctacagt 1500gaattacctt gatggtggtt ctactggggc ttatatatgg ccaggaaact gctagcaaga 1560gaaatatacc ccgagggctg ggcacagtgg ctcacacctg taatcccagc actttgggag 1620gctgaggtgg gcagatcacc tgaggtcaag agttcgagac cagcctggcc aacatggcga 1680aatcctgtct ctactaaaaa tacagaaatt agccgggtgt ggtggcatgc gcctataatc 1740ccagcctctc gggaggctga gggagaagaa ttgcttgaac tcaggaggca gaggttgcag 1800tgagctgtga tcacaccact gcactccagc ctaggagaca gagcaagact ccatctagag 1860agacagagag agagagagag ggagaaatat accccactag ccataataaa gtggcaaaat 1920tttgttttca gaatgcagta ttttaaattt caggtattat tatttttctg agtctctgaa 1980aaatggtttt aaggatttgc ttttaatcct atttacatgt tcacacactc aactacaaat 2040atctttcatt ccttaggtta atatttttca aagggttgtt ctgggaccac ttgcgtgaga 2100atcacctgga ttctgggatg ctttgtgaaa tgaaatgaag attcccgggt ccatacccta 2160ccccctgccc ccaacagcca cagtctcttg ggacagagcc tagaaatctt gcctttgcta 2220agcacctcgg tagattttta tgcacagcaa aggttgagaa ccactacctc ttgttttgct 2280gctgaaagtg ataaaatgtg ccaggaattt tggaagtact tattaagcca atctgaacat 2340caaggagcca tttaagtcag taactcagag gaataagtag agtaaaaatg tcataaactc 2400tcaataaaag caatcaattt aacaccagga gtaataaatg cataaaatga agatgagtta 2460tctaatagag aaattatata aaccatgatt ataactctat atttgagttc ccccttttcc 2520gtaatcagtt aattttctaa aaaatcttcg tcacttaatt ctagcttgat cagatccctt 2580cagtccgtaa ctccctgctc ctcatcttag tttagccctt cttttttctt atgccacctt 2640tcctaaggac cagagaagtg aaatgataat atattggcca cctacaatgt tctagacatc 2700atacatgtat tttctctgct cttctgcata atcactgtga ggcaggcaat actcctccat 2760ttcattgggg aggacattga ggttctgaac tagtgggtca gttgtccttt ttctgaattt 2820gattacccag tagtataaag ctttcttagg taactcacct ttatcacttg ctgactgaat 2880tctgacagat gtcagtttct aattatagcc tggacattca gatgtattca ggaccaagtt 2940gtcctcactc tacctacagg catgaatttc tctcattgac taggttagga gcgccatatg 3000tctgcagcct ccctcagaat cccctgtgtt ctcacaccag ggaactgagg gttccctggg 3060tccttccagg tagaagttca ttgtacaatg aaacatccct taaggaccat ttcatctctt 3120ctttaggtgc atcacacatg gttaaaacaa agtaataaca gaacttagaa tggaatcaaa 3180cagaatgaaa cttacaccaa gtacaattct cattacatta acccagagaa gtgaaaagta 3240gaagaatatt tatttcaagc caatataatt tccaagggct ttgttgaagg ctgaaatctt 3300cgggaggaaa gtagtgagaa gaaaactgtt cattcctcta ttttcccagt atataattgt 3360tttgatcatt ttctttcctt tccagggact aaagacatgt ggaaagccta ctctgacatg 3420aaagaagcca attacaaaaa attcagacaa atacttccat gcttggggga actatgatgc 3480tgtacaaagg gggcttgggg ctgtctgggc tacagaagtg atcaggtaat gcacattcct 3540gatgttgcca ggaatgagtg agcagagctt gactgccttg gacagtcagg agagaggtaa 3600gctccttgca gagaagttag aggctgcagc ccctcctcct cttgccctct ctctgcctgt 3660gtgcttagtg cgagggtctg agtggatggt agaagtgagt gattcctcac cctccctctc 3720tgggtgctgt tcatccagcc taggggtgcc cagcctggct gagtggggca gtgcccaggc 3780agggtcattg ttttcacccc tccttccttg gccttcctgg gcttctccca gagtcctccc 3840ttggaaagca gagaatggga aggtgggctg ttgctcactg gcctggtgat taatctcctt 3900gcttgcctgg actacagcga tgccagagag aacgtccaga gactcacagg agaccatgca 3960gaggattcgc tggctggcca ggctaccaac aaatggggcc agagtggcaa agaccccaat 4020cacttccgac ctgctggcct gccagagaaa tactgagctt ccttttcaat ctgctctcag 4080gagacctggc tgtgagcccc tgagggcagg gacatttgtt gacctacagt tactgaattc 4140tatatcccta gtacttgata tagaacacat aaaaatgctt aataaatgct tgtgaaatcc 4200agtttgttat tggaatctgg aagcagaata tgacagtctt cctgggatca tgggcctgtt 4260tagtaccata gggatgacca ataaac 42866193DNAhomo sapiens 6gttttctgct ccttggtcct gggtgtcagc agccgaagct tcttttcgtt ccttggcgag 60gcttttgatg gggctcggga catgtggaga gcctactctg acatgagaga agccaattac 120atcggctcag acaaatactt ccatgctcgg gggaactatg atgctgccaa aaggggacct 180gggggtctgg gct 193764PRThomo sapiens 7Val Phe Cys Ser Leu Val Leu Gly Val Ser Ser Arg Ser Phe Phe Ser1 5 10 15Phe Leu Gly Glu Ala Phe Asp Gly Ala Arg Asp Met Trp Arg Ala Tyr 20 25 30Ser Asp Met Arg Glu Ala Asn Tyr Ile Gly Ser Asp Lys Tyr Phe His 35 40 45Ala Arg Gly Asn Tyr Asp Ala Ala Lys Arg Gly Pro Gly Gly Leu Gly 50 55 608369DNAhomo sapiens 8atgaagcttc tcacgggcct ggttttctgc tccttggtcc tgagtgtcag cagccgaagc 60ttcttttcgt tccttggcga ggcttttgat ggggctcggg acatgtggag agcctactct 120gacatgagag aagccaatta catcggctca gacaaatact tccatgctcg ggggaactat 180gatgctgcca aaaggggacc tgggggtgcc tgggccgcag aagtgatcag caatgccaga 240gagaatatcc agagactcac aggccatggt gcggaggact cgctggccga tcaggctgcc 300aataaatggg gcaggagtgg cagagacccc aatcacttcc gacctgctgg cctgcctgag 360aaatactga 3699122PRThomo sapiens 9Met Lys Leu Leu Thr Gly Leu Val Phe Cys Ser Leu Val Leu Ser Val1 5 10 15Ser Ser Arg Ser Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala 20 25 30Arg Asp Met Trp Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile 35 40 45Gly Ser Asp Lys Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys 50 55 60Arg Gly Pro Gly Gly Ala Trp Ala Ala Glu Val Ile Ser Asn Ala Arg65 70 75 80Glu Asn Ile Gln Arg Leu Thr Gly His Gly Ala Glu Asp Ser Leu Ala 85 90 95Asp Gln Ala Ala Asn Lys Trp Gly Arg Ser Gly Arg Asp Pro Asn His 100 105 110Phe Arg Pro Ala Gly Leu Pro Glu Lys Tyr 115 12010369DNAhomo sapiens 10atgaagcttc tcacgggcct ggttttctgc tccttggtcc tgagtgtcag cagccgaagc 60ttcttttcgt tccttggcga ggcttttgat ggggctcggg acatgtggag agcctactct 120gacatgagag aagccaatta catcggctca gacaaatact tccatgctcg ggggaactat 180gatgctgcca aaaggggacc tgggggtgcc tgggccgcag aagtgatcag caatgccaga 240gagaatatcc agagactcac aggccgtggt gcggaggact cgctggccga tcaggctgcc 300aataaatggg gcaggagtgg cagagacccc aatcacttcc gacctgctgg cctgcctgag 360aaatactga 36911122PRThomo sapiens 11Met Lys Leu Leu Thr Gly Leu Val Phe Cys Ser Leu Val Leu Ser Val1 5 10 15Ser Ser Arg Ser Phe Phe Ser Phe Leu Gly Glu Ala Phe Asp Gly Ala 20 25 30Arg Asp Met Trp Arg Ala Tyr Ser Asp Met Arg Glu Ala Asn Tyr Ile 35 40 45Gly Ser Asp Lys Tyr Phe His Ala Arg Gly Asn Tyr Asp Ala Ala Lys 50 55 60Arg Gly Pro Gly Gly Ala Trp Ala Ala Glu Val Ile Ser Asn Ala Arg65 70 75 80Glu Asn Ile Gln Arg Leu Thr Gly Arg Gly Ala Glu Asp Ser Leu Ala 85 90 95Asp Gln Ala Ala Asn Lys Trp Gly Arg Ser Gly Arg Asp Pro Asn His 100 105 110Phe Arg Pro Ala Gly Leu Pro Glu Lys Tyr 115 1201210001DNAhomo sapiens 12gggtggatca cgaggtcagg agatcgagac catcttggct aacatggtga aaccccgtct 60ctactaaaaa tacaaaaaaa ttagccgggc gtcatggtgg gcgcctgtag tcccagctac 120tcgggaggct gaggcaggag aatggtgtga acccgggagg cagaacttgc agtgagccta 180gatcgcgcca ctgcactcca gcctggggga caaaacgaga ctctgtctca aaaaaaaaaa 240aaaaaattcc cacattagag ttggggaaat gggcagtcct ggtggaagtt agggaacaga 300tctgggacac gttatagcca gctggactac aggaggccat aagctcaatt cttccttgac 360tctgaaacct tccactggtc ctaatgccta gtaattccag gcctttccca gttgtgccag 420gcttggaggt gaacacatct atgtgccaag aaggaaaggt atgccaagca ggggcttaag 480tcatccttat cctcagtctg tctatgagtg gtatgtaccc ctgttcccct tgcaagatct 540gctgggctta ggtctcctgg ctgtgagttc cccatacctg ggcataaatg tagtgagcct 600gagctcccaa ataaggttgg gggctccaga gaggtggaga gccctgtgtc tgggaagtgt 660gcccacccag caggtctgac caggaagata cactgctagg gttatggaaa aagactatgt 720gtcaaggtct cttgattctc catctaggca gagaatcatc tttaattaat gggaaactgg 780aaggcaaatt acttggacct gaaattactt tttgtttatt gaaccactgt gttgtaaatc 840acatctctct gaaggcaaga gaaatcaggg agttacaaaa tgtttaggag aactaaacag 900gactccctgt tttgctaact aatcagattg agacaggctc tctggtaaat ctacaaattt 960gatgttgttc aaccataagc agtaaatttc ctatgctgga ttttcctgac aatgaatgta 1020aaaggaaaag gagtcttttt gacaaaatat tttattgttc atctaaactg aaaaacttct 1080ctatttttca aaattgctat acgtgtttaa agatgtagat atttgaatag cctaactggt 1140acagaaggtt taatgatgat tcctaagaca tacctataaa ttacttgaaa ttgaaacgaa 1200atttaagaag aattattgga attttcccct tctcaaatga gttcttagtt tcataaatac 1260tatacaagtc cataagagat ttggggtttt gagatgtctt tttttttttt tttttttcag 1320acggagtttc actgttgttg cctaggctgg agtgcaatgg cgtgacctca gctcactaca 1380acctccacct cccaggttca agcgattttc ctgcctcagc ctcccaagta gctgggatta 1440cagggacctg ccacaacgcc aagctaatgt tttgtatttt tagtagagat ggggttcacc 1500atgttggcca ggcttgtctg gaactcctga cctcaggtga tccacccgcc tataatttat 1560tactcccttt tgcaaatgtt tgaaaaggaa taaagtgcaa tatttttaaa cagaatgcag 1620agttctgttg tcctttggca ataccagttt cagactctga gagtggctct tgctgttgcc 1680gacagtgggc tgatgaccaa atcccaacat gcccccgctg cgagtccttc ataacctgat 1740tcagtcatca cttagaggcc agcaggcttc agggaggcgt gagcctcagc caacaaccta 1800taggggaaga gacgcagaac tcaatgcaga caggtttgga ttctggtgcc tagagaatgc 1860aacttggaaa ctctgagcca ggagaaaagg gttctctctc catgagagag tgtgggcttt 1920gtgagaagcg acacacagca aacacaatta agagtccacc cctcagcggg gcgcaggggc 1980tcacgcctgt aatcccagca ctttgggagg ccgaggcggg tggatcacga ggtcaggaga 2040tcaagaccat cctggctaac acagtgaaac cctgtctcta ctaaaaatac aaaaaaatta 2100gccgggcgtg gtggcgggcg cctgtggtcc cagctactcg ggaggctgag gcaggagaat 2160ggtgtgaacc cgggaggtgg agcttgcagt gagccgagat cgcgccactg cactccagcc 2220tgggcgacag agcgagactc catctcaaaa aaaaaaagaa aaagaaaaag aaaaagagtc 2280cgcccctgaa ttaaatagtt ggtccttttg tgttcctggt gattcacttg ctaagtggaa 2340gaaacaggag ggaatctttt ctcctgccct cctggtaatc catagcccat ggcctggctt 2400tacttctgta aagtggcagg agaccttttg acagctgagc catttcttat tttatttatt 2460ttaataagag atggtaggaa tgagcaatga tattagtacc tggggactgt tgttcttaag 2520gagaaacaat cttagaatga ttagtgatac cccttgcttt ctcttttctt tcattatact 2580ttttgtacac atatttttcc catttattta ttggaatctt actgatttat tataagtata 2640agctttatgt ctacacatgt ataatcattt ttccccaagt ataagtctct ttttcatgga 2700ggcacagcct agacctggtt agccgccatc tcccctcatt gtatgcccaa tatctattgt 2760agtatctgct gcatagaagg cactcgatgc gtgaatggat aatgactgat gatgaatcaa 2820taaataaatg gacatgtcat tgtaaaaaat tctaaaaatc tagaataaca caagctgttg 2880gcactaccta gaaacacaga tgtaaaactt cctaggttgt gtttcaccat gggaacatgt 2940ctttgaacaa aaatgggatc atattctatt gcactctttc ccttaagaga tacttctcca 3000ggtcattaag tgctcttcca caatatcagt atatggcaga ggcaaggtca taccaggtct 3060gtctgaaacc agggcttggc tcttaacttg cagccatact gcctccaagt ctaggtggct 3120gggttttagg atctgtaatg ggaactcagt gtcacaacct ctactgggaa ggtattctgg 3180tgttgcataa caggactttc tgttagagat aaccatggca aaatggaata gagacaaagt 3240tcaggtttct gctgccagga gctgagattg ctgtgaccaa tggcattctc ccaaaccaaa 3300taatccaacc tggaattacc ataaaccact cctcatcttt tcaaggggtg tccaagttcc 3360cagaaaagaa catttgttaa gggatggagg caaggaggtg gagaagaaag agcactggcc 3420aaggtatcat gagtgtcctg ggttctggtc cttgaataag ccatttatct tctctgcagc 3480ttctccatct gataggagtt tggaggcaga gttttttctt aatgagcaaa agacagtcgt 3540gcctaggaga tgtggtgtac atgttagaaa gaagggactg gctgtgactc tataaaagat 3600gaattcatac aaaaacaaat taccctttcc cagggagaaa gtttggatcc agtaattaga 3660gatctcaaaa agtagaagac ctgccctgtg aggcctgtgg cctccaagtt tgaatgctgt 3720gtgtcagctt taaaaactag tttcttgctg ataaatgttt catattaagc atgtgttgag 3780agtactcctt gcctaccttc actagccact gtttccttcc cctcctccct tgtcccttca 3840ttctctccag aactttctgc taacttccat tctcttcagg acttcagcat ggttgggaga 3900agatcagaaa ggcatcctca ctgtttttat tttagtccac ttgacctttg gggagtagtt 3960ccactggctc ataagtatca gccccccata gcacagcacc ccacactgag cccggaagca 4020ataaagaatc ccaatctgct gtcactaacc agcacgctca actgccatgc cctttactct 4080tctcatctcc ctgctttcac gtcacaccaa ctaatttctc tatgagtcag cctcaactct 4140cccaacactc tgcccaccct tcttctacta ccttccagtg agctcctcga aagaagggtc 4200tgcggtgagg atgccccttt atctctgcct atttccttcc cattacaaaa acttgaaacc 4260tgcctttccc atgttgattt cactttattc tcatctttac ccatggggta tgcctcctgc 4320aattcctcct agacaataga atgagaaaga ggggtcctcg tcctctttgc tttccatgac 4380catttctcca ttcttcacct ctgtgatgtg tcctctttga agtccctgat aaattcatta 4440ccaccttctc tccagtctta ctaatgttat ctgcacaagt gatttccaaa caggaagatt 4500ttcaaacact gattcctgaa gatcaccccc aactcgctga actgagacca agacctccaa 4560gattatggct taggaatctg catttttttt ttttttttga gacaagagtc tcgctctgtt 4620gccaggctag agtgcaatgg tggaatcata gctcattgta acctcaaact cctgggctca 4680agtgatcttc ctgcctcagc ctcccaagta gtgaggacaa caggagtgtg ccaccatgcc 4740cagctaattg ttaatttttt gtagaaatgg agtctcacta tgttgctcgg gctggtctca 4800aactcctgac cttaacccat cctccgcctc cgcccccaaa agtgttggga ttacaggtgt 4860gagccaccgt gcccagccta gaaataccca ctagaagctt ctgtgtagac aatctgctta 4920gtgatgtttg gagacaaagt acctctttat tgtattcatt gacaaaactc tccagtcctc 4980tcccatcttc atggaaaatt ttcacagttc atttacggcc ctctttccaa cacattcact 5040gccaatactc ttattgacaa taactgtatt gttgaacctt

ccagtatcct gcattcccgg 5100atcaaggccc cctcaaagcc ctgatatgca aatatctggg aaaagaatgt tccagaggaa 5160aggaacagct aatccgaggc ccctagggta agatgtgcct gggggtttgg agaccagtgt 5220ggccagagca aaatgagcag gaggagagaa ttggatgatg aggtacgaga ggaaggagtt 5280aggacagttt gagtaaagtt tgaaaaccat tataagggct ttgacttcaa ctatgagtgg 5340aagtggaatc ctccggagag ttttgaatgg agagtgatag aagttgtctt gtgttgtaac 5400agtctggctg ctatactgaa aagagactag ttggcggcaa agggggaaat gtggaagcca 5460gttaagaagc catcataacc cagaaggtga tgcctaataa catctctctg ggagcagcgg 5520agagatgata agggtttgcc ttctgaatat gttttttgac aattaatgta aacatttcaa 5580gtaggctgag attttattgc atattaacaa tgtccatgtt cactcgcggc agccgccccc 5640ttctgcgcgg tcatgccgag ccagcacctg ggcctggaac tgggccgcag cccccagctt 5700cacccaccac ctccctacca tggacccctg caaagtgaac gagcttcggg cctttgtgaa 5760aatgtgtaag caggatccga gcgttctgca caccgaggaa atgcgcttcc tgagagagtg 5820ggtggagagc atgggaggta aagtaccacc tgctactcag aaggctaaat cagaagaaaa 5880taccaaggaa gaaaaacctg atagtaagaa ggtggaggaa gacttaaagg cagacgaacc 5940atcaactgag gaaagtgatc tagaaattga taaagaaggt gtgattgaac cagacactga 6000tgctcctcaa gaaatgggag atgaaaatgt ggagataacg gaggagatga tggatcaggc 6060aaatgataaa aaagtggctg ctattgaagt cctaaatgat ggtgaactcc agaaagccat 6120tgacttattc acagatgcca tcaagctgaa tcctcgcttg gccattttgt atgcaaagag 6180ggccagtgtc ttcgtcaaat tacagaagcc aaatgctgcc atccaagact gtgacagagc 6240cattgaaata aatcctgatt cagctcagcc ttacaagtgg cgggggaaag cacacagact 6300tctaggccac tgggaagaag cagcccatga tcttgccttt gcctgtaaat tggattatga 6360tgaagatgct agtgcaatgc tgaaagaagt tcaacctagg gcacagaaaa ttgcagaaca 6420ttggagaaag tatgagcgaa aacatgaaga gcgagagatc aaagaaagaa tagaacgagt 6480taagaaggct caagaagagc aggagagagc ccagagggag gaagaagcca gacgacagtc 6540aggagctcac tatggccctt ttccaggtgg ctttcctggt ggaatgcctg gtaattttcc 6600cggaggaatg cctggaatgg gaggggacat gcctggaatg gccggaatgc ctggactcaa 6660tgaaattctt agtgatccag aggctcttgc agccatgcag gatccagaag ttatggtggc 6720cttccaggat gtggctcaga acccagcaaa tatgtcaaaa taccagagca acccaaaggt 6780tatgaatctc atcagtaaat tgtcagccaa atttggaggt caagcataat gcccttctga 6840taaataaagc cctgctgaag gaaaagcaac ctagatcacc ttatggatgt cgcaataata 6900caaaccaacg tacctctgac cttctcatca agagagctgg ggtgctttga agataatccc 6960tacccctctc ccccaaatgc agctgaagca ttttacagtg gtttgccatt agggtattca 7020ttcagataat gttttcctac taggaattac aaactttaaa cactttttaa atcttcaaat 7080atttaaaaca aatttaaagg gtctgttaat tcttatattt ttctttacta atcattgtgg 7140atttttcctt aaattattgg gcagggaata tacttattta tggaagatta ctgctctaat 7200ttgagtgaaa taaaagttat tagtgcgagg caaacataaa aaaaaaaagt ccatgttcat 7260ctctaaatga catcattgtt ccaaagcttt tccattcttc ttaaccttcc acctgtcaat 7320ctataggaga tgacttctcc tacttcactc atgcattgac tccttcaatc aataaaagtg 7380actaagaacc tgctacaggt gaggtgctgt gtttggtgtt aaagtgacaa cagttatctg 7440tcaataagcc tgacaaggtt cctatccctg tgttttgtgc actctgggtc aaactcagaa 7500atgcaaacag gtggagagcg atgagttcta tgactggtaa agaaaagggc ctgctggttt 7560ccctcaggat ctctgtcctt catctcaaaa tgcatcttcc ttgttatcgt tcctctcctt 7620cctgtctcag aggaagacct gctcctgcta cactctgggc aaccttgtcc ccgtggccct 7680gtggcccctt ggttgttgaa gtctatgtta tgccctatct tttaccctca gtcactctct 7740ctgttaacat tctccctgtg ccctgtaacc ctccctcatc tttaaataaa tcctcctcct 7800ttgaccttcg catgtattca gtcatgcaac tcaacaagca tttattgcac agtgatattc 7860aatttgccac ttgctaaaag tctgaacctt ggcagctgaa tgtgatcaga aaaaaagcac 7920gactgctatg actagtctca ctttaaattc atggtcgttg accaagagct accatacaat 7980ccactacctt tctcaagttc agtcacattc ttcctttcct agatgtctgc tttctacttc 8040tcttctcttc tgaaacttcc cacaactcct cgttcattct cttctcagtt gacaactttg 8100cttcctattt cactgaaaaa tagaagcaat cagatatgaa cttctggctg ggcatggtag 8160ctcatgccta taatctcagc actttgggag gccaaggcag gaggactgca ggttaggaat 8220ttgagaccag cctgggcaac atggtgaaac tcccactgta ctaaaaattt taaaaattac 8280tcaaacatat tggcaaacaa ctgcagtccc agctacttgg gaggttgaga tgcaaggatc 8340acttaaacct gggaggctga ggctgcagtg agccatgatt gcaccactgc actccagctc 8400aggcaacaga gcaagaccct gtcttgagag gagaggagaa gagaggaggg gaggggaggg 8460caggggaggg gaggggaggg gaagggagag gggaggggag aggggaggag agaggggagg 8520ggaggggagg ggaggggagg ggaggagagg aggatcaggt gaggagtatg ccaaggagtg 8580tttttaagac ttactgtttt ctctttccca acaagattgt catttccttt aaaaagtagt 8640tatcctgagg cctatattca tagcattctg aaagaaagaa aagaaaagag gaaagaaaga 8700gagaggaagg aaggaaggag aaagagagag gaaggaagga gaaagagaga ggaaggaagg 8760gaggaagaga agaagggagg aagaaaagaa ggaaggaagg agggagggag ggaagggagg 8820gagggaaaga ggaagaaagg agggaaagaa ggaaggaaga gagagaggaa ggaaggagga 8880agagagaaga aggaaggagg aagacagaga gggagtaagg aaggaaggaa ggagaaagag 8940agaggaagga agaaatgaag gaaggaagga aagaaagaaa aaataaaaga gtgaaaacgg 9000actggagaag aagaaaccac agttgctgct atatccacca gcctctctgc atgtcctggc 9060ctcagccctg ctgggctctg gtactgacca cttccttcct tcctaatttc ctaattgact 9120aggccagctg agcagggctt ttctgtgctg aggaggtaaa tctctggata tctagactga 9180ggggtggaag gagccttcca gggcacacat gagacatggc aggggtaggc tgctagtttt 9240attttgtttt cttttagaca cagggtcttg ctctgttaac caggctggag tgcagtggcg 9300tgattatagc tcactgcagc cttgacctcc tgggtctccc acaatccttc cgcttcagcc 9360tcttgagtag ctgggactgc aggtgcacac taccacaccc ggtccattta tttttatatt 9420tcgtagagac aagatcttac agttttgcac agagtgatct taaactcttg accccaagtg 9480atcctcctgc cttggcctcc aaaagcattg ggattatagg agtgagccac tgtgctggac 9540ctagtctgtc agctttgaag ctttagatat gaactcagag ggacttcatt tcagaggcat 9600ctgccatgtg gcccagcaga gcccatcctg aggaaatgac tggtagagtc aggagctggc 9660ttcaaagctg ccctcacttc acaccttcca gcagcccagg tgccgccatc acggggctcc 9720cactctcaac tccgcagcct cagccccctc aatgctgagg agcagagctg gtctcctgcc 9780ctgacagctg ccaggcacat cttgttccct caggttgcac aactgggata aatgacccgg 9840gatgaagaaa ccactggcat ccaggaactt gtcttagacc gttttgtagg ggaaatgacc 9900tgcagggact ttccccaggg accacatcca gcttttcttc gctcccaaga aaccagcagg 9960gaaggctcag tataaatagc agccaccgct ccctggcagg c 100011310001DNAhomo sapiens 13gtctgccagg gagaggtggc tgctatttat agtgagcctt gctggtctct tgggagggaa 60gaaaagctgg atgtggtccc tggggaaagt ccctgcaggt catttcccct acaaactggt 120ctaagacaag ttcctggatg ccggtggttt cttcatcccg ggtcatttat cccagttgtg 180taacctatgg gaacaagaga ggtttgctgt gccttggcaa tggacagggt gctagatcag 240ctctgctcct cagcattggg ggaagtgcag ctgcagagat gccagtggga gccccgtgat 300ggcggcacct gggctgctgg aaggtgtgga gtgagggcag ctcttcagcc agctcctgac 360tataccggtc atttcctcag gatgggccct gctgggccac atggcagatg accctgactg 420aaatccctgt gagttcatgt ctaaagcttt aagctttaaa acggacagcc tacccctgcc 480acatctcatg tgtgccctgg aagcctcctt ccacccctct ggatgtcctg atatttctca 540gcacagaaaa tctctgctcc gctggcttag ccaatttgga aatgcttttt ctaagttggc 600tcctgagcca aggacaatgt agagaggggg actttctgct gccccagcct agtcctggag 660ccccaccttg ggagaatgag agtgtggtgc gttaaatagg cagcccagct ggggacgtgc 720ccagcatcca ggcagggaag ggtgggagag ctcttggtct gctgtattat cacggagggg 780tgcagggggc atgcagatca ctctctcatg agaacatcaa cagggtcaga ttagctctgc 840agaggcttat ggaggagcat ggtggccaga gatgggtcag taccagagcc caggggggct 900gaggccagga catgcagaga ggctggtgga catagcagca actctggttt cttcttctcc 960agtccatgtt cataccctga gggctaggca tttgtaataa caaacaaaca agcaatttag 1020aaatgggcca ggcatggtgg catgtgccta tagtcccagc tacttgggag gccaaggcag 1080gaggcctgct tgaacccaga aatttgaggc cagcctgggc aacacagcaa gattatctta 1140aaaaattttt tttaatctct gagaaatggg tagggccagg aagtaaagga tggccaaata 1200ctccataagc agcaaatgcg tggctccaat gtgaacaatg atattataga ctctgttctg 1260agacctatgc attgacacct ccacctcccc cactacatct tgccacctta aaaccactga 1320gagtggtacc tgctggaatg ggtccacaca cacagtcaca catattttag gcagggtagt 1380tgacatcccc agggaaaaag agctcacaga gagaggctga atgtttccaa ctgggtagca 1440gtaatagtac atcatgctgt acatggtaca gcacagatca ggtgaaaata atagcacatc 1500gtgattaacc agggcttatt ccagggagtc aagaagagtt tcatatcaga aaaatctatc 1560tttgtaattc actataccag taatcaaaga aaaggattgt acatttattt tactagatgc 1620agaaaatgaa tttcataatt gtcaacatct actgatgata aggaaaatgt ataacaaaat 1680aaagagacca tttctgactt gagaaaggat aaataccaat atgttatagc aacagttctc 1740aaactgtttt ccagggaacc ctaagaatcc ctccttaggg aggctttgat ctcaaaatta 1800tttttagaat agtgctaaca cactattttc atgtttcagt ctcattttct catgagtaca 1860cacaatatga caagttagtt gatatgagtg tggatttcca catggtaact gacttttcag 1920aagctaccac ttgttgagtt tggtataata tagaatagcc acaattatct aaaaatacca 1980ttaaaataca ctcccccatt tcaactatat atctgtgtga ggctgaattt tcttcatata 2040ctccaaccta aataacatat taaaacaggt tggatgatga atcagatagg aaaatccagc 2100tatgaaaaaa aaatcagaca tgaaaaattt tcaaaagggt aaaaccatag tactcttctt 2160actttttttc ttttggaaga tggttatttt tcataaaaat atattattta tgttaacata 2220tagaagatgg ataatttttt gaagaattga taaatgttta aattttttct ttctattatg 2280gtaaatactg atgaatagag tccccataaa taaaagttct ttggggtatt caataatttt 2340taatagtgta atgggatcct gagaccaaaa ggtttgagaa tcattgctct acagcaaaca 2400ttatgtgtaa ttaagacact tcaggtgcat tctcaagaag accaataaag aggccacaat 2460ggcaggcgtg gtggctcaca cttgtaatcc aagaacttag agaggacgag gcaggtggat 2520cactggaggt caggaattct caaccagcct ggccaacatg gtgaaaccct gtctctacta 2580aaagtacaaa aattagtcgg gtgtagtggc aggtacctgt aatcccaagt acttgggggg 2640ttgaggcagg agaatcactt gaagccggga ggtggaggct gcagtgagcc gagatcgtgc 2700cactgcactc cagcctgggc aacggagtga gacttcatca tggaaaaaaa aacaaagagg 2760ccaggatgtc tggttgttac tgccactgtt tcacatatcc ctgaaggacc tgcccaatgc 2820taaagaaaca caaggaaggt aagaggtgaa agagaagaaa tgaaactatc attgtttgaa 2880gatgacacca tcttttacat agaaaacctg ttagaatcaa atggcaagct attagaacta 2940ctaagagaat tcagtgaggc tgctgtattc atggcaaaat tttaacaatt gatagcattt 3000ctctgcaaca ttccttaata gttataaaat acagcacaaa gtagtaccaa aaatattaac 3060tatctaggaa ataacctctt acagagaaaa tttagtctgt taaaggataa acagtggcaa 3120tgtacgtcat gtccacagag attatatttt agcttagcaa agataccaat tctcccaaat 3180ttatttataa attaaatgca atgtgaatca aaatttccca ctggaatttt tatcaggaag 3240gcaacaaatt ctttctttct ttctttcttt ctttctttat ttatttattt atttatttat 3300ttatttattt ccttccttcc ttccttcctt ccttccttcc tttctttctt tctttctttc 3360tttctttctt tctttctctc tctctttctc tctccccccc tctctctctc tctgtctctc 3420tctctctctc tttctttctt tctttctttc tttcttttta agacaaagtc tggctctgtc 3480acccaggctg cagtgcagtg atacaatctc agctcactga aacctcaacc tctccggcat 3540caggtgaacc tcccacctca gccccccgag tagctgggac tacaggtgca caccactggg 3600cctagataac tttttgtatt tattgtaaat aaacacaaaa aataaatatt ttgctcaggt 3660tggtctggaa ctcctgggct caagcaatcc gcctgccttg gcctcccaaa gtgctagaat 3720tacagttgtg agccaccaca cccagccaat aaattaattc tttatgatga ataagttatc 3780tatgaaaatt aagtcagctg ggtgcggtgg ctcacgcctg taatcccagc actttgccgg 3840gctgaagcag gtggatcacc tgaggttggg agttcaagac cagccggacc aacatagaga 3900aaacccgtct ctactaaaaa tgcaaaatta gctgggtgtg gtggcatatg cctgtaatcc 3960cagatactta ggaggctgag gcaggagaat tgcttgaacc cgggcggtgg aggttgcggt 4020gagccaagat tgcaccattg cactccagcc tgggccacaa gagcgaaact ccatctcaaa 4080aaaaaaaaaa gagaagttaa gtcaatgaaa agttaagtca attaaaaaag taagagctgt 4140agtgtttaga tatatacaca cacacatata tatatattta tctttatata tgtatatata 4200tcttttcctt tttttgagac cgagtctgtt tttgttgccc aggctggaat gcagtggcgc 4260gatctctgct tactgcaacc tctgcctccc aggttcaagc gattctcgtg cctcagcctc 4320ccgagtagct gggattacag gtgcctgccc ccatgcccgg ctaatttttg catttttagt 4380agagacgggg tttcaccatg ttggccaggc tggtctcaaa ctcctgacct caggtgatcc 4440accggcctca gcctcccaaa gtgctgggat tacaggtgtg agccaccgcg cccagccata 4500tattttgctt ttcatctgca gctcctggat cctaactcct tgttatattg ttgggcactt 4560taggcctcag taaacagaat ctctgtctat gaccttctcc tgtccttctt ccacctgccc 4620aaagcaggac tctaatttga ttgtgggtca aaagactctc attccagaaa gggccttgcc 4680tcatacccta gaggaaggaa tgctgcacag aaacgccaag tctgaacaga caagccttgc 4740tgggtttata ccatatgctt tttgtccaat cacatttctt catggttgcc aatcatgcct 4800atgtaatgaa gcctccataa gaacccagaa ggacagggtt cagagagttt ccacatagct 4860gaacactatc tggagagtga acacttccta gagagtggca cacccagaga gatcatgaaa 4920gctccacgcc cctttcccct tacctcgccc tccacatctc ttcatctgta tctttcataa 4980tatcctttat aaataaacca gcaaatgtgt ttccctgagt tatgtgagtc actctagcaa 5040attaatcgaa cccaaagagg gggtcatggg aaccccaact tgaagccagt cagtcagaag 5100ttccagaggc ccagacttgc aactggggag aaagaggggg aggtcttggg gactgagccc 5160ccaacctgtg ggatctgaca ctgtctccag gtaggtagtg ttggaactgc attggaggac 5220actcctggtg tctgctgctt ggtgtgtggg gggaaaaacc cacacctttg gttacggagg 5280tcttctgtgt tgacgatcat tgctgtttga gggcagaggg aatacacggt ttgagagagt 5340ttttccctga catgagcgaa caggggacat gtactggtct ctgagatggg ggatcatggg 5400atctgccaca agtggggaga ccactgtgac ccctgccaca gtctttgggg cagagggtgt 5460ctcgggggca gaagaagcga gagttgtttg cagtagcagt tatgtccaaa gtgggcgcca 5520ggaaagtagg gctgcccagc tttgaagagc ctccttactc ccagcctgaa tgaaaccatt 5580tcctgtaaag cgctaagcat aaagtttgcc aatggtgatc cacggagaag tgagtgtacc 5640ccaccccgcc atcccacagg gaatgtcgga gtgatgttga tctgcaccta gggaaggaat 5700ggttcatgag atgtggtgga gatgctgagg gcccgtggac atcagatcct accctacctg 5760tgccaggaca agccatgcgc atgtgcttca gaccaccagg caacaggagt gttgcatgag 5820gtgtgaagca ggcacctggg aaagaggagt gtgaacagca gatgggacac actgggggca 5880gtcataggaa tgaaatgtcc caggatggat gcaggcaggt tatggaggac ttagtgagga 5940ctgctctcct ggtgggaatt gtggagtggg agactggatg gagactggag gtgttttaag 6000tagggaagcc aacttgcaag ggtgaccagg gaaactatgt cggccaaggg tgagacatgc 6060actggcaaga ctctcagaca gcctggctta tctaagcaga atgcttgagc catgccaacg 6120gtgcctcgca agttgtatta atcatgtcct ttcattttgt gtttttggtg cttggcatct 6180gggcccttgc tgaccctaag ggaccatttc tctcagagct agtcaagtcc tagacacagt 6240aaatgactct cctgggagca tgccttccat gtgcagacca accaatcaag agtccacact 6300cccacccacc tcctttatcg agctctcaca tcctggggca ccatccacct gccctaatca 6360ctcaaggacc acgtcccaaa caactaggga cagcctccat gcccctgcac ccattgaaat 6420tattcatgct agccaatcct aaacctgtgt atgctgccac accattcctt cctgcagaaa 6480cacagtaagg actcttccta cacctcccct acttcctctg ctccctgact tacccactta 6540cttcctggtg cagtcccctg tggcatagtt cactctcttc ttttgggaac tgtgaggcta 6600tcttctcaat ggcagtcatc tcctgagctg ttggccttgc catacctaac taataataaa 6660atctatattc taaggtaaaa acaaaacaga tagggtctca ctctgttgcc caggctggag 6720tacagtggtg tgatcatgac tcactgcagc ctcaaactcc tgggctcaag cagttctctc 6780atctcaacct cccgagtagc tgggactaca ggcacacacc accatgcctg gctagttttc 6840ttattttttt tgtagataca gggtcttgtt atgttgccaa ggctggtctt gaactcctgg 6900gctcaagtga tcctcctgcc ttggcctccc aaactgctgc aattacaggc atgagccacc 6960atgcccagat cagaaatctt actaaaaata tttcaaggag aagagaaagc caaagatgtt 7020gaatatatat atatgtgtgt gtgtgtgtgt gtatatatat gtatatatgt gtatatatgt 7080gtgtatatat atatgtatat atgtatatat atatgtatat atgtatatat atatgtatat 7140tggggcaggc gtggtggctc atgcctgtgg tcctaactac ttgagagtct gaggtgggag 7200gattgcttga gcctgggaga tcgaggctgc tgtgagctga gactacacca ctgcactcca 7260gcttgggtga cagagtgaga ccctgtctcc aaaaaaacaa aaagaaaaag aaaaaaagat 7320ggaaaaagac atgaaaaaac aacaacagaa atacccacac atcatcaatg ggagggaagc 7380atcttgaggc agcaaagcgg gagtgctagt agagaggcag atagggcgtt ggacctgagg 7440cattaaggaa agtcaggatt tggagcttac aagtctctca ttggagatgg gatggggttg 7500gaatgaatgt ctgagcaaac acaaagcatt tccttcccta atgactcccc accagtctaa 7560agaatcccac attaggtcga acacggtggc tcacgcctgt aatcccagca ctttgggagg 7620ccaaggcggg tggatcacga ggtcaggaga tcgagaccat cttggctaac atggtgaaac 7680cccgtctcta ctaaaaatac aaaaaaatta gccgggcgtc atggtgggcg cctgtagtcc 7740cagctactcg ggaggctgag gcaggagaat ggtgtgaacc cgggaggcag aacttgcagt 7800gagcctagat cgcgccactg cactccagcc tgggggacaa aacgagactc tgtctcaaaa 7860aaaaaaaaaa aaattcccac attagagttg gggaaatggg cagtcctggt ggaagttagg 7920gaacagatct gggacacgtt atagccagct ggactacagg aggccataag ctcaattctt 7980ccttgactct gaaaccttcc actggtccta atgcctagta attccaggcc tttcccagtt 8040gtgccaggct tggaggtgaa cacatctatg tgccaagaag gaaaggtatg ccaagcaggg 8100gcttaagtca tccttatcct cagtctgtct atgagtggta tgtacccctg ttccccttgc 8160aagatctgct gggcttaggt ctcctggctg tgagttcccc atacctgggc ataaatgtag 8220tgagcctgag ctcccaaata aggttggggg ctccagagag gtggagagcc ctgtgtctgg 8280gaagtgtgcc cacccagcag gtctgaccag gaagatacac tgctagggtt atggaaaaag 8340actatgtgtc aaggtctctt gattctccat ctaggcagag aatcatcttt aattaatggg 8400aaactggaag gcaaattact tggacctgaa attacttttt gtttattgaa ccactgtgtt 8460gtaaatcaca tctctctgaa ggcaagagaa atcagggagt tacaaaatgt ttaggagaac 8520taaacaggac tccctgtttt gctaactaat cagattgaga caggctctct ggtaaatcta 8580caaatttgat gttgttcaac cataagcagt aaatttccta tgctggattt tcctgacaat 8640gaatgtaaaa ggaaaaggag tctttttgac aaaatatttt attgttcatc taaactgaaa 8700aacttctcta tttttcaaaa ttgctatacg tgtttaaaga tgtagatatt tgaatagcct 8760aactggtaca gaaggtttaa tgatgattcc taagacatac ctataaatta cttgaaattg 8820aaacgaaatt taagaagaat tattggaatt ttccccttct caaatgagtt cttagtttca 8880taaatactat acaagtccat aagagatttg gggttttgag atgtcttttt tttttttttt 8940ttttcagacg gagtttcact gttgttgcct aggctggagt gcaatggcgt gacctcagct 9000cactacaacc tccacctccc aggttcaagc gattttcctg cctcagcctc ccaagtagct 9060gggattacag ggacctgcca caacgccaag ctaatgtttt gtatttttag tagagatggg 9120gttcaccatg ttggccaggc ttgtctggaa ctcctgacct caggtgatcc acccgcctat 9180aatttattac tcccttttgc aaatgtttga aaaggaataa agtgcaatat ttttaaacag 9240aatgcagagt tctgttgtcc tttggcaata ccagtttcag actctgagag tggctcttgc 9300tgttgccgac agtgggctga tgaccaaatc ccaacatgcc cccgctgcga gtccttcata 9360acctgattca gtcatcactt agaggccagc aggcttcagg gaggcgtgag cctcagccaa 9420caacctatag gggaagagac gcagaactca atgcagacag gtttggattc tggtgcctag 9480agaatgcaac ttggaaactc tgagccagga gaaaagggtt ctctctccat gagagagtgt 9540gggctttgtg agaagcgaca cacagcaaac acaattaaga gtccacccct cagcggggcg 9600caggggctca cgcctgtaat cccagcactt tgggaggccg aggcgggtgg atcacgaggt 9660caggagatca agaccatcct ggctaacaca gtgaaaccct gtctctacta aaaatacaaa 9720aaaattagcc gggcgtggtg gcgggcgcct gtggtcccag ctactcggga ggctgaggca 9780ggagaatggt gtgaacccgg gaggtggagc ttgcagtgag ccgagatcgc gccactgcac 9840tccagcctgg gcgacagagc gagactccat ctcaaaaaaa aaaagaaaaa gaaaaagaaa 9900aagagtccgc ccctgaatta aatagttggt ccttttgtgt tcctggtgat tcacttgcta 9960agtggaagaa acaggaggga atcttttctc ctgccctcct g 10001141209DNAhomo sapiens 14cagggctggg cggcggcggc ggcggcggtc atggaacgcc aagaggagtc tctgtccgcg

60cggccggccc tggagaccga ggggctgcgc ttcctgcaca ccacggtggg ctccctgctg 120gccacctatg gctggtacat cgtcttcagc tgcatccttc tctacgtggt ctttcagaag 180ctttccgccc ggctaagagc cttgaggcag aggcagctgg accgagctgc ggctgctgtg 240gaacctgatg ttgttgttaa acgacaagaa gctttagcag ctgctcgact gaaaatgcaa 300gaagaactaa atgcgcaagt tgaaaagcat aaggaaaaac tgaaacaact tgaagaagaa 360aaaaggagac agaagattga aatgtgggac agcatgcaag aaggaaaaag ttacaaagga 420aatgcaaaga agccccagga ggaagacagt cctgggcctt ccacttcatc tgtcctgaaa 480cggaaatcgg acagaaagcc tttgcgggga ggaggttata acccgttgtc tggtgaagga 540ggcggacttg ctcctggaga cctggacgca gaggcccgtc atctggcgga tgaggctaag 600aatcttgtta gtgtcacttt tgacattagc aagatgaacc cttaaccctc gattcaattg 660ccttacgcac gcttttcaca gtgactagcc aaggggaggt ggggttgatt tctgttccta 720actacacctg catatgtcag ggctccagtc agcaaaaggt atagatgttg cctctaggca 780tgaggtcatt ggtcacattc tacttggaga cagtgattgc attcattgat ttcatggtta 840attgctagtt ggtaggtaaa ggcctctaga tgattagcaa tcttgataaa agaggcctag 900taatgttctt ttgaggttag aaatccttgc tgctaggaca gtctctgtga caggttgcgt 960tgaatgatgt cttccttatc aatggtgagc ccaccagtga ggattactga tgtggacagt 1020tgatggggtt tgtttctgta tatttatttt tatgtacaga actttgtaaa aacgaaacta 1080tttaaaaaac aagaataaca tttttagcat ctttattcaa ggagatttat ggacttcaat 1140ttgtctatca aacattaaat agctttttat tacaacctcc aaaaaaaaaa aaaaaaaaaa 1200aaaaaaaaa 120915204PRThomo sapiens 15Met Glu Arg Gln Glu Glu Ser Leu Ser Ala Arg Pro Ala Leu Glu Thr1 5 10 15Glu Gly Leu Arg Phe Leu His Thr Thr Val Gly Ser Leu Leu Ala Thr 20 25 30Tyr Gly Trp Tyr Ile Val Phe Ser Cys Ile Leu Leu Tyr Val Val Phe 35 40 45Gln Lys Leu Ser Ala Arg Leu Arg Ala Leu Arg Gln Arg Gln Leu Asp 50 55 60Arg Ala Ala Ala Ala Val Glu Pro Asp Val Val Val Lys Arg Gln Glu65 70 75 80Ala Leu Ala Ala Ala Arg Leu Lys Met Gln Glu Glu Leu Asn Ala Gln 85 90 95Val Glu Lys His Lys Glu Lys Leu Lys Gln Leu Glu Glu Glu Lys Arg 100 105 110Arg Gln Lys Ile Glu Met Trp Asp Ser Met Gln Glu Gly Lys Ser Tyr 115 120 125Lys Gly Asn Ala Lys Lys Pro Gln Glu Glu Asp Ser Pro Gly Pro Ser 130 135 140Thr Ser Ser Val Leu Lys Arg Lys Ser Asp Arg Lys Pro Leu Arg Gly145 150 155 160Gly Gly Tyr Asn Pro Leu Ser Gly Glu Gly Gly Gly Leu Ala Pro Gly 165 170 175Asp Leu Asp Ala Glu Ala Arg His Leu Ala Asp Glu Ala Lys Asn Leu 180 185 190Val Ser Val Thr Phe Asp Ile Ser Lys Met Asn Pro 195 2001610907DNAhomo sapiens 16tgagcagcct gagatgtcag taattgtagc tgctccaagc ctgggttctg ttttttagtg 60ggatttctgt tcagatgaac aatccatcct ctgcaatttt ttaaaagcaa aactgcaaat 120gtttcaggca cagaaaggag gcaaaggtga agtccagggg aggtcagggg tgtgaggtag 180atgggagcgg atagacacat cactcatttc tgtgtctgtc agaagaacca gtagacactt 240ccagaattgt cctttattta tgtcatctcc ataaaccatc tgcaaatgag ggttatttgg 300catttttgtc attttggagc cacagaaata aaggatgaca agcagagagc cccgggcagg 360aggcaaaagt cctgtgttcc aactatagtc atttctttgc tgcatgatct gagttaggtc 420accagacttc tctgagcccc agtttcccca gcagtgtata cgggctatgt ggggagtatt 480caggagacag acaactcact cgtcaaatcc tccccttcct ggccaacaaa gctgctgcaa 540ccacagggat ttcttctgtt caggtgagtg tagggtgtag ggagattggt tcaatgtcca 600attcttctgt ttccctggag atcaggttgc ccttttttgg tagtctctcc aattccctcc 660ttcccggaag catgtgacaa tcaacaactt tgtatactta agttcagtgg acctcaattt 720cctcatctgt gaaataaacg ggactgaaaa atcattctgg cctcaagatg ctttgttggg 780gtgtctaggt gctccaggtg cttctgggag aggtgaccta gtgagggatc agtgggaata 840gaggtgatat tgtggggctt ttctggaaat tgcagagagg tgcatcgttt ttataattta 900tgaattttta tgtattaatg tcatcctcct gatcttttca gctgcattgg gtaaatcctt 960gcctgccaga gtgggtcagc ggtgagccag aaagggggct cattctaaca gtgctgtgtc 1020ctcctggaga gtgccaactc attctccaag taaaaaaagc cagatttgtg gctcacttcg 1080tggggaaatg tgtccagcgc accaacgcag gcgagggact gggggaggag ggaagtgccc 1140tcctgcagca cgcgaggttc cgggaccggc tggcctgctg gaactcggcc aggctcagct 1200ggctcggcgc tgggcagcca ggagcctggg ccccggggag ggcggtcccg ggcggcgcgg 1260tgggccgagc gcgggtcccg cctccttgag gcgggcccgg gcggggcggt tgtatatcag 1320ggccgcgctg agctgcgcca gctgaggtgt gagcagctgc cgaagtcagt tccttgtgga 1380gccggagctg ggcgcggatt cgccgaggca ccgaggcact cagaggaggt gagagagcgg 1440cggcagacaa caggggaccc cgggccggcg gcccagagcc gagccaagcg tgcccgcgtg 1500tgtccctgcg tgtccgcgag gatgcgtgtt cgcgggtgtg tgctgcgttc acaggtgttt 1560ctgcggcagg tgaatgacgg gcgtgggtcg gtgcgcgctc ggcttgcgca cacggtgtct 1620ctataagtgc gcgggtgacg agagtcggga tgtgccggag accccggggc ggagagcggg 1680attacaagta caggaatccc tggtcacgct ccccgcccct ggaaacccag ctggggcgag 1740ggagggcgtg gacgggaccg ttctgggagc tcgcctttgg ctgcggttgg ctccaggccc 1800caggcgcagt ttgctcgcgg cgtggggatg aagtccgtgt ccctggaggg gcccaggaag 1860ggcgaggaaa gcggagtgga gtaagttcgt ctaggatcgg tcccgggtgg ctctgggatc 1920caatctgcgc cgccctggcc caggtcccag gttcaggtcc tttacgccac tgtgtccacc 1980acctggctga gcgctgaggt cagcgcgggc tgtttcctgg cccttgggaa tgtgccagga 2040cccgtcccct aaggactagc gaggaggtga ctcactgtga caaggagacc ccagggaacg 2100gactgtatga ggtcagaacc ccgcccggga tggggtacag cgggactcca gaagccctct 2160cccctgcccc ttcgcggtct ccgtcctccc atcggcacag tgacctattt ggctggaaca 2220gtttgttccc aaggaagccg ggcactggag gtccgggaca ccgcgtcggg tccccgctcc 2280gcggcgcgct gtaggggtcg gggagtcacg gccctgcgct gggcgggctc taaccagcct 2340gtcagtcggg gaagggcaag ggtctcctct acctctttcc caccgcggcc gggagaatcg 2400cggcccagcc tgtcctcggg tcggggcgct ggactccggg gcgggagcgg agcccacgcc 2460tggatgggag gcggggaggg ttcatgtctt tgaggggtgg ggggtctggg gggcacgacg 2520ctgctcaggg cctctatcag ctgcctcggg ggctcagggc ttcccgacct agcccagatt 2580ccctctccga aagctacagg gctgagcgga gcaggggggc gagtcgcccc ctggggcgcc 2640gccgcctggc gcggaccaca gcgcgtcctc tccgtcccaa acccctgggg gacacttgcg 2700ccctcttcgt gaggaaaagc atcttggagc tgggttagga acttggggcg cccaggcagc 2760ttcccctctc cttgcctccc tccacgtcgc gtttctggga ggacttgcga gcggttttgt 2820tttcgttgct cccgtctatt tttattttcc agggatctga ctcatcccgt gctttgggcg 2880tggagataag gtggaggggc cggctcccgg cgcgcgcgcg cgtgcgtgtc tgcgcgggcg 2940tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtctg tgtcagagac ggcacaagag 3000cgcgcggttt cccaacagcg gcgggagttt cggaagcctg gccggctcag cgtgacgtgt 3060tcgcggcccc ccggtcccct cccattctcc ccctccccac cccagggtga cgcgcagccg 3120gagtggaagc agagttttgg cgggcgagca gcgccttgca ggaaactgac tcatcactac 3180tccctccagc ggtccgaggc tctgcccacg cacctcccac tccgcgcgtg atttcctgga 3240ggccggcgcc ccctcccggc cctggcggga atagcacaca ggctttcccg cggagtgggg 3300ctggccggcg cgaaccgccg cggctactcc tgggctcatc cgagatcaac ccctatgcca 3360ttaccacccc ttcaaaggag cactccttag gttcaacagt attcactgag ctcttactgg 3420aaattaaaat atggctgaag tctaaggcag gaaggccaat aaaggaggct atttttaatt 3480gtttctaaaa caagggtttg cgtttctgag ttttctttgg gctgaaagtt attatgagca 3540tgagagcaga ttttgatggg ggaggagagg cctatgagag ccataagaga aggaggggtg 3600gtagaagagg agagggtgcc tgcctagatc ctagtcctgt cttgaactcc cgagagccag 3660ggaatatcca gctccttgat gaagccctag gcgggcgcct cctccttgtg cctatgatgt 3720attgagaccc agaatgtcca tttcaaacat accagtgtgt ctccgcttgg ctggcacccc 3780aagagtgccc atctgaggaa ttgtgccaaa cacttgcttg aatcttcaat ttggattaag 3840ttggtctcgg gaggcagggc ctcagcaatc tatattttga aaaaactccc taggtgcttt 3900tctttctttc tttctttctt tctttctttc tttctttctt tctttctttc tttctttctt 3960tctttctttt tctttctttc tttctttttc tttcttttct ttctttcttt ctttctttct 4020ttctttcttt ctttctttct tcctttctct ttctctcttt ctttctcttt ctctctttct 4080ttcttttctt tcgacagagt tgcactctgt cacccaggct ggagtgcaat ggcaccatcc 4140tggactcaag tagtcctcct gtttcagcct cccaagtaac cgggaccaca ggcgtgatcc 4200ccccgccccc atgcccagat tttttttttt tttttttttt ttttgagatg cggtctcgct 4260ctgtcaccca ggctggagtg cagtggcgtg atctcggctc actgcaagct ccgcctcccg 4320ggttcacgcc attctcctgc ctcagcctcc cgagtagctg ggactacagg tgctgccatc 4380atgcccggct aatttttttt tgtattttta gtagagacgg gggtttcacc gtgttagcca 4440ggatggtctc aatctcctga cctcgtgctc cgccctcctc ggcctcccaa agtgctggga 4500ttacaggtgt gagacactgc acccaaccac ccagctaatt tttatttatt tttattttta 4560gtagagacag ggtctcagct agttgcccag gctagtcttg gacccttggg ctcaaatgat 4620tctcccacct ctgcctccca gagtattagg attacaggca taagccactg cccctggcct 4680ccccaagtga ttgtgatggg cctctctggt taagaaacct caaaattaga gagggagtgg 4740ggttcaatac tacagcacag gactcagggc aaacaggcct gggttcagat cctggctgtg 4800ccacttatga actgtgtgat gttaggcaag ttacttaact tatctgagcc ttggttgcct 4860cttctgtaaa aagggagcta atagatatcc actttttagg aggattgata tttttaaact 4920gcttagaaca gcccccaaac ataaaaatat ataaataaat cccaactcat gcctagcaga 4980gggtggatag aggttatttg agggctctgt ccactgtact gggtgacccc tttatggggc 5040agtggccttt ggccttttta gctgtatgac tcaggggcaa gtctcatatc tcttccatct 5100cctgcccttt aaacttggtg tgaagttacc aagagcctcc tctcccaacc agctgggacg 5160tgaaactgtg ggctccactg atcacaagca gtggggtgag gtggggtgga gcagatgtgg 5220catgtgtccc gggcttcctg cctcatgagg actcagcaga gctttcaccc ccagaaactg 5280caagttggga cttgtcccta ggaaaatcca gttgctgcca aggtcgtgca gtcactcagc 5340cctggagtca agccagagca ggcaggtagg tgccagggct ccctcatggg caaactcact 5400ctccgttttc cctctcctga agggggagga gaggagccag gtagaccagc cacctttaat 5460tttctttttg cctgcaaaac ggtttccttg gacacaggca acacgaggca ggggctgcca 5520ggtgtctaga cttcagatca cctgatgtgc ctggcaggat gtggctcagc ctgggagaaa 5580tcatcccttg cgctgccccg cccggcccct ccttacccct aggccacccg cctgacgaca 5640tccttgggaa aggccctcag cctacagcac ctgtcagctg ctgtctgaag gaggtagttg 5700gcagggggaa gtgatagggg ggaggctcag taaaactgaa ggcagagagg aataatcata 5760cttctgtttt caatgcactt ctctatacga agtgctgctg gcacgttacc tacattaact 5820cagttaattc tcatgtctat cctctgagac agtcactatt actatcccca ttttatagat 5880gaggaaacta gagctcagac aagttaagtt gcttgcccag ggtcacctag taaaacctgg 5940actccagccc aggtgatctg gctccagagc cctcctgctt aaccaccagg atacagcctt 6000tcattcagct ctgttctgtc tgccttgctg catggactct gtgatcaatt tcttgagtat 6060gtgtctgtag ccatgctctt taaacttgta catggcccca tttatggatg aggaaactga 6120gacctagaga cattaagtgg ctttttaaag cttacgtagt aactggcaga gctaggacca 6180caacccgggt gctttttgcc ccaaagtccc gggtactttt acttggcaga gcagggttac 6240cctacttggg gatctgggtc gggggactta ggaggctgga ggaactgtca gactgtttct 6300tcttttggga attgaccttc tggccagggc tgcgattagg aaactgctgg actctggcaa 6360ttcacacata tttggggggc attcacaccc atgagggaca cctctggggg gaaaacaaat 6420tgattttagc tgataatacc tggtggcaaa caggaccctg gtccttgctc ttgcaataga 6480cttgcctttg ttgacattag cttgcccttc agttgcctgc tctcccagtg accttggtgt 6540gccaggctgg ctgagctctg ctggtggggg tcaggcctcc tgtgggaagg aagcaggaag 6600accagctgga aggagtgaga gagaccctct ggtaggaaga cgtcacctga ggtgacacag 6660caaagcccgg ccaggtaaca tagtgtctaa tctccgccgt gaccagggcc ttccttgtat 6720ctctgctgca ggcgccatgt cagaaccggc tggggatgtc cgtcagaacc catgcggcag 6780caaggcctgc cgccgcctct tcggcccagt ggacagcgag cagctgagcc gcgactgtga 6840tgcgctaatg gcgggctgca tccaggaggc ccgtgagcga tggaacttcg actttgtcac 6900cgagacacca ctggagggtg acttcgcctg ggagcgtgtg cggggccttg gcctgcccaa 6960gctctacctt cccacggggc cccggcgagg ccgggatgag ttgggaggag gcaggcggcc 7020tggcacctca cctgctctgc tgcaggggac agcagaggaa gaccatgtgg acctgtcact 7080gtcttgtacc cttgtgcctc gctcagggga gcaggctgaa gggtccccag gtggacctgg 7140agactctcag ggtcgaaaac ggcggcagac cagcatgaca ggtgcggaca tgtgcacgga 7200aggactttgt aagggaccag gattctcaga atccatggtc caagggctga cctgtctggt 7260cctggtccag catgctccag gtagaaggaa acaggcccag agaggggaag caacctccct 7320gaggtcacac agcaagtagg cagcaaagac caactagcta acatttattg ggaatgttca 7380ttatgccagg ccctttgcca agcttctaag gtagatttat ttagtcctta tagcaatgtt 7440ataacataag acattcttgt caccctgccc gcctttcttt ttgagacagg tgtcttaact 7500ctgttggcca gactggagtg cagtgatacg atcatggctc actgcagctt caaactcctg 7560ggctcaagcg atcttcctac ctcagcctcc tgggtagctg ggaagctggg actatagttg 7620tacaccacta cgcccggtta attttttgag tttttgtaga gacaaggtct caccatgttg 7680cccgggctgg tcttgaactc ctgagctcaa gcagtcctcc tgcctcagcc tcccaaagtg 7740ttgtgattac aggcgtgagc caccatgccc agccccttgc catcctttta gggcaaggaa 7800accaggctca gagaggtaga gtgatttatc taaggtctca aagtgaattt gccgttgggt 7860caagactaat tataataaca acaactactg acgtttatat gggcccggca ttgtgctgaa 7920cactttcatg gattttgtaa cagaatccct agatcagcac tgtccagtaa ctctgcaggg 7980atgggagtgt ccggtacagg ggccacgagc cacatacggc tgttgtgcat ttgacacaca 8040gctcatgtga ctgaggaact gaattgttca ttttatttga ttgtagtctg tttaaacaag 8100cacacagagc tagtagtggt tcctctgctg ggcagcttga cttagagcag acccatgggt 8160gcgggtgcgg tgatggataa aatcacatct gtgaagcatg gtgggacact ccataatacc 8220cctcaagaga cagagtggac gttccccgag ttcttcctgt tctcagcagt cggccccatt 8280ggccccaggg aagggtgtcc tggcccccca ctgtcttcct cagttgggca gctccgccgc 8340gtcctcttct tcttggcctg gctgacttct gctgtctctc ctcagatttc taccactcca 8400aacgccggct gatcttctcc aagaggaagc cctaatccgc ccacaggaag cctgcagtcc 8460tggaagcgcg agggcctcaa aggcccgctc tacatcttct gccttagtct cagtttgtgt 8520gtcttaatta ttatttgtgt tttaatttaa acacctcctc atgtacatac cctggccgcc 8580ccctgccccc cagcctctgg cattagaatt atttaaacaa aaactaggcg gttgaatgag 8640aggttcctaa gagtgctggg catttttatt ttatgaaata ctatttaaag cctcctcatc 8700ccgtgttctc cttttcctct ctcccggagg ttgggtgggc cggcttcatg ccagctactt 8760cctcctcccc acttgtccgc tgggtggtac cctctggagg ggtgtggctc cttcccatcg 8820ctgtcacagg cggttatgaa attcaccccc tttcctggac actcagacct gaattctttt 8880tcatttgaga agtaaacaga tggcactttg aaggggcctc accgagtggg ggcatcatca 8940aaaactttgg agtcccctca cctcctctaa ggttgggcag ggtgaccctg aagtgagcac 9000agcctagggc tgagctgggg acctggtacc ctcctggctc ttgatacccc cctctgtctt 9060gtgaaggcag ggggaaggtg gggtcctgga gcagaccacc ccgcctgccc tcatggcccc 9120tctgacctgc actggggagc ccgtctcagt gttgagcctt ttccctcttt ggctcccctg 9180taccttttga ggagccccag ctacccttct tctccagctg ggctctgcaa ttcccctctg 9240ctgctgtccc tcccccttgt cctttccctt cagtaccctc tcagctccag gtggctctga 9300ggtgcctgtc ccacccccac ccccagctca atggactgga aggggaaggg acacacaaga 9360agaagggcac cctagttcta cctcaggcag ctcaagcagc gaccgccccc tcctctagct 9420gtgggggtga gggtcccatg tggtggcaca ggcccccttg agtggggtta tctctgtgtt 9480aggggtatat gatgggggag tagatctttc taggagggag acactggccc ctcaaatcgt 9540ccagcgacct tcctcatcca ccccatccct ccccagttca ttgcactttg attagcagcg 9600gaacaaggag tcagacattt taagatggtg gcagtagagg ctatggacag ggcatgccac 9660gtgggctcat atggggctgg gagtagttgt ctttcctggc actaacgttg agcccctgga 9720ggcactgaag tgcttagtgt acttggagta ttggggtctg accccaaaca ccttccagct 9780cctgtaacat actggcctgg actgttttct ctcggctccc catgtgtcct ggttcccgtt 9840tctccaccta gactgtaaac ctctcgaggg cagggaccac accctgtact gttctgtgtc 9900tttcacagct cctcccacaa tgctgaatat acagcaggtg ctcaataaat gattcttagt 9960gactttactt gtaatattac tattgtggtt attatacctt ataagaacaa ataaatgggc 10020ttttgggaag gatttcataa ttaaataatt ttaaaaatta agcatttaaa tttagagaat 10080gcagaaaact tagcaaacag aaagactgct gcaaaaaaca acagcaaaac aaaaactact 10140gtcacacctc tgcaaagatc accaatgtca atattttggt ttgttgtgta atctttttgt 10200aaagaatata ttatagctta acatcattat tcatcagata aatgcaaatt aagataccac 10260aataagatac caccatacac ttaccagaat gattaaaaaa gactgacagt gccaagcatt 10320ggcaaggtta tggagcaact ggatctctta tttaaaaaaa ctgtttgggc cgggcgcagt 10380ggctcacacc tagaatccca gtgcttcggg aggctgaggc aggagatcac ttgaggccaa 10440gggttcaaga ccagcctggc caacatggtg aaatctctac taaaaataca aaaattagct 10500gggcatggtg gtgcacgctt gtaatcccag ctacttggaa ggctgaggtg ggaggatcac 10560ttgaacccag gaggcagagg ttgcagtcag ctgagatcat accactgtac tccagcctct 10620tccagggtga cagtgagatt catctcaaat aaatacataa ataaaaaact gtttggtaat 10680atcttctaaa gatgcctacc ttcatggcta cctcatgacc cagtaattct attcctggac 10740atgttctcga gagaaatgag ttcatatttc cactgaaaaa ggcataagaa tgttctacac 10800agtggctcac acctataatc ccagcacttt gggaggctaa ggcaggagga cggcttgagc 10860ccaagagtgt gagaccagtt tgggcaacat agcgagactc ttatctc 1090717164PRThomo sapiens 17Met Ser Glu Pro Ala Gly Asp Val Arg Gln Asn Pro Cys Gly Ser Lys1 5 10 15Ala Cys Arg Arg Leu Phe Gly Pro Val Asp Ser Glu Gln Leu Ser Arg 20 25 30Asp Cys Asp Ala Leu Met Ala Gly Cys Ile Gln Glu Ala Arg Glu Arg 35 40 45Trp Asn Phe Asp Phe Val Thr Glu Thr Pro Leu Glu Gly Asp Phe Ala 50 55 60Trp Glu Arg Val Arg Gly Leu Gly Leu Pro Lys Leu Tyr Leu Pro Thr65 70 75 80Gly Pro Arg Arg Gly Arg Asp Glu Leu Gly Gly Gly Arg Arg Pro Gly 85 90 95Thr Ser Pro Ala Leu Leu Gln Gly Thr Ala Glu Glu Asp His Val Asp 100 105 110Leu Ser Leu Ser Cys Thr Leu Val Pro Arg Ser Gly Glu Gln Ala Glu 115 120 125Gly Ser Pro Gly Gly Pro Gly Asp Ser Gln Gly Arg Lys Arg Arg Gln 130 135 140Thr Ser Met Thr Asp Phe Tyr His Ser Lys Arg Arg Leu Ile Phe Ser145 150 155 160Lys Arg Lys Pro

Claims

1. A method for treating glaucoma, said method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising an agent that interacts with a gene encoding a serum amyloid A (SAA) receptor (SEQ ID NO:12), wherein said interaction decreases the expression of SAA (SEQ ID NO:1 or SEQ ID NO:3).

2. A method for treating glaucoma, said method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a Tanis antagonist.

3. The method of claim 2, wherein said agent is a peroxisome proliferator-activated receptor α (PPARα) agonists, tachykinin peptides and their non-peptide analogs or α-lipoic acid.

4. The method of claim 3, wherein the agent is fenofibrate, Wy-14643, (4-chloro-6-(2,3-xylidino)-2-pryrimidinylthiol)-acetic acid), ciprofibrate, 2-bromohexadecanoic acid, bezafibrate and ciglitizone, bafilomycin or concanamycin.

5. A method for treating glaucoma, said method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a p21 antagonist.

6. A method for treating ocular hypertension, glaucoma or age-related macular degeneration, said method comprising administering to a patient in need thereof, a therapeutically effective amount of an agent that down-regulates expression a tanis gene (SEQ ID NO:14) or p21.sup.Waf1/Cip1/Sd1 gene (SEQ ID NO:16).

7. A pharmaceutical composition comprising a therapeutically effective amount of a Tanis antagonist and a pharmaceutical carrier.

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