Our Providers

Konstantin Petrukhin, PhD
  • Associate Professor of Ophthalmology at CUMC
Konstantin Petrukhin, <span>PhD</span>

Pharmacological inhibition of lipofuscin accumulation in the retina - Experimental and clinical imaging data indicate that high levels of lipofuscin induce degeneration of RPE and the adjacent photoreceptors in atrophic AMD retinas. In addition to AMD, dramatic accumulation of lipofuscin is the hallmark of Stargardt’s disease (STGD), an inherited form of juvenile-onset macular degeneration. The major cytotoxic component of RPE lipofuscin is a pyridinium bisretinoid A2E. A2E formation occurs in the retina in a non-enzymatic manner and can be considered a by-product of a properly functioning visual cycle. Given the established cytotoxic affects of A2E on RPE and photoreceptors, inhibition of A2E formation could lead to delay in visual loss in patients with dry AMD and STGD. Partial visual cycle inhibition with small molecule drugs may reduce the formation of A2E in the retina and prolong RPE and photoreceptor survival in patients with dry AMD and STGD. Using the grant support form the new NIH initiative, the Blueprint Neurotherapeutics Network, Dr. Petrukhin’s lab is working on optimization of a non-retinoid lead compound that acts as an inhibitor of bisretinoid formation in the retina. In addition, we are conducting evaluation of novel drug targets for pharmacological inhibition of retinal lipofuscinogenesis. 

Photoreceptor protection - Atrophic AMD is a slowly developing neurodegenerative disease in which photoreceptors in the central part of the retina are lost due to apoptosis. Delaying or preventing the loss of photoreceptor cells in the macula would predictably lead to delay in AMD progression. Nuclear receptors comprise a family of transcription factors involved in regulation of a variety of biological processes including cell survival. Ten percent of the most widely used drugs are nuclear receptors modulators indicating the importance of this group of ligand-dependent transcription regulators as drug targets. NR2E3, also known as PNR and RNR, is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the adult and developing retina. Physiological ligands for NR2E3 remain to be identified. Mutations in NR2E3 have been associated with several forms of retinal degeneration in human patients. It has been suggested that in addition to its role in retinal development, NR2E3 may be involved in photoreceptor maintenance in the adult retina. The phenotype of the late-onset, slowly progressing retinal degeneration in rd7 mice, which harbor a spontaneous deletion within the Nr2e3 gene, seems to be consistent with the dual function of this nuclear receptor in retinal development and photoreceptor maintenance. The expression profiling experiments in Dr. Petrukhin’s laboratory suggest that NR2E3 directly regulates the genes that may be involved in protection of the retina from oxidative stress. Using NIH funding, Dr. Petrukhin’s laboratory is conducting the screen for synthetic NR2E3 ligands that may potentially become a treatment for atrophic AMD. 

Downregulation of gliotic response in the retina - Gliotic response in the retina is a sequala of many retinal diseases including atrophic AMD. Muller glial cells are responsible for the extraordinary range of functions within the retina such as mediation of photoreceptor survival, synthesis and renewal of visual pigment, neurotransmitter recycling, removal, and protection of neurons from potassium toxicity. Given the fact that Muller cells are significantly involved in the processes of retinal dystrophy and taking into account examples of successful neuroprotection in CNS by downregulation of reactive gliosis, it is plausible that reduction of Muller cell gliosis may represent a new therapeutic area in atrophic AMD. Gliotic response in Muller cells is triggered in part by impaired retinal K+ homeostasis associated with downregulation of Kir4.1 channels responsible for release of potassium from Muller cells into circulation. Reduced ability of damaged retina to buffer potassium elevates intra-retinal K+  level and induces Muller cell swelling which was shown to stimulate dedifferentiation and proliferation of Muller cells. A fluorenone drug known as DPOFA, (R)-(+)-(5,6-dichloro 2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetic acid, was shown to be highly effective in inhibiting K+-induced swelling in CNS astrocytes. The drug demonstrated significant efficacy in preventing mortality in animal models of concussive brain injury and was systemically administered to humans in Phase I clinical trials for trauma-induced brain edema. As gliotic response in retinal Muller cells and CNS astrocytes may have overlapping, if not identical, mechanisms we hypothesize that DPOFA (or its derivatives) may be used as an anti-gliotic therapy in patients with dry AMD. Dr. Petrukhin’s laboratory is performing evaluation of DPOFA and its analogs in in vitro and in vivo systems modeling gliotic response in the retina in order to develop rationale for the use of fluorenone drugs as a treatment for atrophic AMD.

Staff

Current
Nicoleta Dobri, PhD – Postdoctoral Research Scientist
Boglarka Racz, PhD – Postdoctoral Research Scientist
Pavel Izerovich, PhD – Associate Research Scientist
Alan Zhou – Research Technician
Patricia Murphy – Senior Secretary

Past
Sarah Zimov, Ph.D. Postdoctoral Research Scientist
Fabiana Fonseca, Ph.D. Postdoctoral Research Scientist
Igor Chernov, Ph.D., Visiting Scientist
Cornelius Saunders, Student Intern
Qiong Qin, M.D., Ph.D., Postdoctoral Research Scientist

This provider does not accept new patients

Lab Locations

  • Edward S. Harkness Eye Institute Research Annex

    160 Fort Washington Avenue
    2nd Floor, Room 204
    New York, NY 10032
    Phone:
    (212) 305-9040
    Email:
    kep4@columbia.edu

Research Interests

  • Identification of small molecule treatments for dry AMD in three target areas: reduction of accumulation of toxic pyridinium bisretinoids in the RPE, stimulation of photoreceptor survival, and inhibition of reactive gliosis in retinal Muller cells

NIH Grants

  • PHARMACOLOGICAL MODULATION OF THEVISUAL PHOTOTRANSDUCTION CASCADE FOR TREATMENT OF DIABETIC RETINOPATHY (Federal Gov)

    May 1 2017 - Apr 30 2019

    PHARMACOLOGICAL TREATMENTS FOR STARGARDT DISEASE (Private)

    Jul 1 2015 - Jun 30 2018

    THERAPEUTIC APPROACHES FOR ABCA4-ASSOCIATED DISORDERS (Federal Gov)

    Aug 1 2011 - Jul 31 2017

    SMALL MOLECULE DRUGS FOR TREATMENT OF DRY AGE-RELATED MACULAR DEGENERATION (Federal Gov)

    Jul 1 2011 - Jun 30 2017

    ADVANCED RPB4 ANTAGONIST AS A DISEASE MODIFYING AGENT OR DIABETIC RETINOPATHY (Private)

    Jan 1 2016 - Dec 31 2016

    PRE-CLINICAL EFFICACY OF THE OPTIMIZED RBP4 ANTAGONISTS IN THE ANIMAL MODEL OF MACULAR DEGENERATION (Private)

    Jan 1 2016 - Dec 31 2016

    SMALL MOLECULE DRUGS FOR TREATMENT OF DRY AGE-RELATED MACULAR DEGENERATION (Federal Gov)

    Jul 1 2011 - Jun 30 2016

    EVALUATION OF SMALL MOLECULE NR2E1/TLX MODULA (Private)

    Apr 1 2010 - Apr 1 2012

Publications

  • Dobri N, Qin Q, Kong J, Yamamoto K, Liu Z, Moiseyev G, Ma JX, Allikmets R, Sparrow JR, Petrukhin K. A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis. Invest Ophthalmol Vis Sci. 2013, 54:85-95
  • Qin Q, Knapinska A, Dobri N, Madoux F, Chase P, Hodder P, Petrukhin K. In Pursuit of Synthetic Modulators for the Orphan Retina-Specific Nuclear Receptor NR2E3. J Ocul Pharmacol Ther. 2013, 29:298-309
  • Iserovich P, Qin Q, Petrukhin K. DPOFA, a Cl-/HCO3- exchanger antagonist, stimulates fluid aB.S.orption across basolateral surface of the retinal pigment epithelium. BMC Ophthalmol. 2011 Nov 15;11(1):33.
  • Webber AL, Hodor P, Thut CJ, Vogt TF, Zhang T, Holder DJ, Petrukhin K. Dual role of Nr2e3 in photoreceptor development and maintenance. Exp. EyeRres. 2008, 87:35-48
  • Petrukhin K New therapeutic targets in atrophic age-related macular degeneration. Expert Opin. Ther. Targets. 2007, 11(5): 625-639
  • Kapitskaya M, Cunningham ME, Lacson R, Kornienko O, Bednar B, Petrukhin K. Development of the High Throughput Screening Assay for Identification of Agonists of an Orphan Nuclear Receptor. Assay and Drug Development Technologies. 2006, 4 (3): 253-262
  • Raz-Prag D, Vasireddy V, Farris RN, Majchzrak S, Mandal MNA, Bush RA, Webber AL, Salem N, Ayyagari R, Petrukhin K, Sieving PA. Haploinsufficiency is Not the Key Mechanism of Pathogenesis in a Heterozygous Elovl4 Knockout Mouse Model of STGD3. Invest Ophthalmol Vis Sci 2006, 47(8):3603-3611
  • Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa D, Austin CP, Gould RJ, Ayyagari R, Petrukhin K. A five base-pair deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature Genetics 2001, 27 (1): 89-93.
  • Marmorstein AD, Marmorstein LY, Rayborn M, Wang X, Hollyfield JG, Petrukhin K. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VM.D.2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2000, 97 (23): 12758-63.
  • Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C Identification of the gene responsible for Best macular dystrophy. Nature Genetics 1998;19(3):241-7
  • Shah A.B., Chernov I., Zhang H.T B M Ross, K Das, S Lutsenko, E Parano, L Pavone, O Evgrafov, I A Ivanova-Smolenskaya, G Annerén, K Westermark, F H Urrutia, G K Penchaszadeh, I Sternlieb, I H Scheinberg, T C Gilliam, and Petrukhin K. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlations and functional analyses. Am. J. Hum. Genet., 1997, v61, p. 317-328.
  • Petrukhin K., Fischer S,G., Pirastu M., Tanzi R.E., Chernov,I., Devoto M., Brzustowitcz L., Cayanis E., Vitale E., Russo J.J., Matseoane D., Boukhgalter B., Wasco W., Figus A.L., Loudianos J., Cao A., Sternlierb I., Evgrafov O., Parano E., Pavone L., Warburton D., Ott J., Penchaszadeh G., Scheinberg I.H., and Gilliam T.C. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genetics, 1993, v.5, p. 338-343.
  • Tanzi R.E., Petrukhin K., Chernov I., Pellequer J.L., Wasco W., Ross B., Romano D.M., Parano E., Pavone L., Brzustowicz L.M., Devoto M., Peppercorn J., Bush A.I., Sternlieb I., Pirastu M., Gusella J.F., Evgrafov O., Penchaszadeh G.K., Honig B., Edelman I.S., Soares M.B., Scheinberg I.H., and Gilliam T.C. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genetics, 1993, v.5, p. 344-350.