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Natik Piri, Ph.D.

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Los Angeles, CA 90095

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Department / Division Affiliations
Associate Professor and Member, Ophthalmology
Member, Brain Research Institute, Jules Stein Eye Institute, Neuroscience IDP

The main directions in my research are: defining the mechanisms leading to retinal ganglion cell (RGC) degeneration in glaucomatous neuropathy; developing strategies for preserving RGCs against neurodegeneration; and identifying/characterizing the genes critical for RGC function/integrity and for morphological/functional differences between various types of RGCs. Different types of RGCs have been identified based on their morphological and physiological characteristics. Undoubtedly, this variation in RGC morphology and function is supported at the molecular level, particularly at the level of gene expression. Current knowledge of RGC molecular biology is very limited. To address this issue, we have initiated a study with the primary aim of identifying genes expressed in RGCs. We were able to isolate a pool of the RGC-expressed genes and the characterization of these genes is under way. We believe that the characterization of RGC-expressed genes is fundamentally important for a better understanding of normal RGC physiology and pathophysiology. Changes in the physiological expression levels of these genes in response to external or intracellular stimuli or the presence of mutations that affect the structure/function of the encoded proteins could undermine RGC viability and, consequently, may be associated with glaucomatous or other optic neuropathies. The degeneration of RGCs and their axons in the optic nerve is a hallmark of glaucoma that affects millions of people world-wide and, if left untreated, could lead to severe visual impairment. The cause of RGC degeneration in glaucoma is unknown, making it impossible to develop appropriate therapeutic strategies. We have analyzed retinal gene expression profiles from the rat glaucoma model with the aim of identifying factors involved in the initiation and execution of RGC apoptosis. Our results implicated several members of the crystallin superfamily in this process, including alpha crystallins. Stress-induced crystallin expression is commonly viewed as an activation of the cell survival mechanism. We showed that the overexpression of alpha crystallins in RGCs significantly increases their survival rate in the optic nerve axotomy model. These results suggest that the downregulation of crystallin genes that we observed in glaucomatous retinas decreases the survival properties of RGCs and thus leads to their degeneration. The role of crystallins in RGC degeneration in response to ocular hypertension is under investigation. Another project in this direction is to investigate the involvement of oxidative stress on RGC damage in optic neuropathies and to identify ways to alleviate its effect. Oxidative stress has been implicated in a variety of neurodegenerative diseases such as Alzheimer?s, Parkinson?s, Huntington?s, and amyotrophic lateral sclerosis. We demonstrated the involvement of oxidative stress and proteins of the thioredoxin system, particularly in RGC degeneration in the glaucoma model and showed the neuroprotective effects of these proteins against glaucomatous RGC death. Studies that provide new information about the RGC death process are essential for understanding the etiology and pathogenesis of glaucoma and for developing strategies to target the cause of the disease.


Munemasa Y, Kwong JK, Caprioli J, Piri N. Alpha A and alpha B crystallins protect retinal ganglion cells from degeneration after optic nerve axotomy. Invest. Ophthalmol. Vis. Sci 2009; 50: 3869-3875.
Munemasa Y, Kim SH, Ahn JH, Kwong JM, Caprioli J, Piri N. Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma. Gene Ther 2009; 16: 17?25.
Verardo M, Viczian A, Piri N, Akhmedov NB, Knox B, Farber B. Regulatory sequences in the 3? untranslated region of the human cGMP-phosphodisterase beta-subunit gene. Invest. Ophthalmol. Vis. Sci 2009; 50: 2591-2598.
Munemasa Y, Kwong JK, Kim S, Ahn J, Caprioli J, Piri N. Thioredoxins 1 and 2 protect retinal ganglion cells from pharmacologically induced oxidative stress, optic nerve transection and ocular hypertension. Adv. Exp. Med. Biol 2009; In press.
Kim SH, Munemasa Y, Kwong JM, Ahn JH, Mareninov S, Gordon LK, Caprioli J, Piri N. Activation of autophagy in retinal ganglion cells. J. Neurosci. Res 2008; 86: 2943 - 2951.
Souied EH, Reid SN, Piri NI, Lerner LE, Nusinowitz S, Farber DB. Non-invasive gene transfer by iontophoresis for therapy of an inherited retinal degeneration. Exp. Eye Res 2008; 87: 168-175.
Munemasa Y, Kim SH, Ahn JH, Kwong JM, Caprioli J, Piri N. Protective effect of thioredoxins 1 and 2 in retinal ganglion cells after optic nerve transection and oxidative stress. Invest. Ophthalmol. Vis. Sci 2008; 49: 3535-3543.
Piri N, Song M, Kwong J.M.K., Caprioli J Modulation of alpha and beta crystallin expression in rat retinas with ocular hypertension-induced ganglion cell degeneration. Brain Research 2007; 1141: 1-9.
Piri N, Kwong JMK, Song M, Caprioli J Expression of hermes gene is restricted to the ganglion cells in the retina. Neurosci. Lett 2006; 405: 40-45.
Piri N, Kwong JM, Song M, Elashoff D, Caprioli J. Gene expression changes in the retina following optic nerve transection. Molecular Vision 2006; 12: 1660-1673.
Piri N, Mendoza E, Akhmedov NB, Farber DB The role of the 5' and 3' untranslated regions of the rod photoreceptor cGMP-phosphodiesterase in mRNA translation. Exp. Eye Res 2006; 83: 841-848.
Piri N, Gao Y, Danciger M, Mendoza E, Fishman GA, Farber DB A transition of G to C in the 5' untranslated region of the cone cGMP-phosphodiesterase gamma subunit and cone-rod dystrophy. Ophthalmology 2005; 112: 159-166.
Piriev N, Yamashita CK, Shih J, Farber DB Expression of functionally active cone photoreceptor cGMP-PDE alpha' subunit in chinese humster ovary, 293 human embryonic kidney and Y79 retinoblastoma cells. Molecular Vision 2003; 9: 80-86.
Piri N, Yamashita CK, Shih J, Akhmedov NB, Farber DB Regulation of rod photoreceptor cGMP-phosphodiesterase alpha and beta subunits expression: mRNA and protein levels. J. Biol. Chem 2003; 278: 36999-37005.
Piriev N, Akhmedov NB, Chang B, Rapoport A, Hawes NL, Nishina PM, Nusiniwitz S, Heckenlively JH, Roderick TH, Kozak CA, Danciger M, Davisson MT, Farber DB A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in rd7 mouse. Proc. Natl. Acad. Sci. USA 2000; 97: 5551-5556.
Guillonneau X, Piriev N, Danciger M, Kozak CA, Cideciyan AV, Jacobson SG, Farber DB A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum. Mol. Genet 1999; 8: 1541-1546.
Gao YQ, Danciger M, Longmuir R, Piriev N, Zhao DY, Heckenlively JH, Fishman GA, Weleber RG, Jacobson SG, Stone EM, Farber DB Exon screening of the gene encoding the alpha' subunit of cone cGMP-phosphodiesterase in patients with various forms of retinal degeneration. Invest. Ophthalmol. Vis. Sci 1999; 40: 1818-1822.
Reid SNM, Akhmedov NB, Piriev N, Kozak CA, Dancinger M, Farber The mouse X-linked juvenile retinoschisis cDNA: expression in photoreceptors. Gene 1999; 227: 257-266.
Akhmedov NB, Piriev N, Perce-Kelling S, Acland GM, Aguirre GD, Farber DB Canine cone transducin gamma gene and cone degeneration in cd dog. Invest. Ophthalmol. Vis. Sci 1998; 39: 1775-1781.
Piriev N, Shih JM, Farber DB Defective RNA splicing resulting from a mutation in the cyclic guanosine monophosphate-phosphodiesterase beta-subunit gene. Invest. Ophthalmol. Vis. Sci 1998; 39: 463-470.
Akhmedov NB, Piriev N, Ray K, Acland GM, Aguirre GD, Farber DB Structure and analysis of transducin beta3-subunit, a candidate for cone degeneration in the cd dog. Gene 1997; 194: 47-56.
Gao YQ, Danciger M, Zhao DY, Blaney J, Piriev N, Shih J, Jacobson SG, Heckenlively JH, Farber DB Screening of the PDE6B gene in patients with autosomal dominant retinitis pigmentosa. Exp. Eye Res 1996; 62: 149-54.
Piriev N, Viczian AS, Ye J, Kerner, B, Korenberg, JR, Farber DB Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha' subunit (PDEA2) and its chromosomal localization to 10q24. Genomics 1995; 28: 429-435.
Viczian AS, Piriev N, Farber DB Isolation and sequence analysis of the human cone cGMP-phosphodiesterase alpha' subunit cDNA. Gene 1995; 166: 205-211.
Piriev N, Khramtsov NV, Lipkin VM Cloning and characterization of the gene encoding the cGMP-phosphodiesterase gamma-subunit of human rod photoreceptor cells. Gene 1994; 151: 297-301.
Piriev N, Yamashita C, Samuel G, Farber DB Rod Photoreceptor cGMP-phosphodiesterase: Analysis of alpha and beta subunits expressed in human kidney cells. Proc. Natl. Acad. Sci. USA 1993; 90: 9340-9344.