Jayakrishna Ambati
- Email: ja9qr@Virginia.EDU
- Phone: 434-924-7876
- Fax: 434-924-9416
Primary Appointment
Professor, Ophthalmology
Education
- Fellowship, Retina Clinical & Research, Massachusetts Eye & Ear Infirmary
- Residency, Ophthalmology, University of Rochester
- MD, Medicine, SUNY Downstate Medical Center College of Medicine
Research Disciplines
Biomedical Engineering, Experimental Pathology, Immunology, Microbiology, Neuroscience
Research Interests
Understanding the Molecular Basis of Macular Degeneration in Order to Hasten the Eradication of Blindness
Research Description
Alu RNA transcripts promote advanced dry age-related macular degeneration:
Geographic atrophy (GA) is the advanced form of dry age-related macular degeneration and is a leading cause of blindness in the Unites States. Currently, there is no FDA approved therapy for the over 1 million Americans with GA. One major goal of the laboratory was to identify novel molecular targets to fight this major unmet health need. We recently identified a class of RNA molecules - Alu RNA transcripts - cause RPE degeneration, which is a critical step in the pathogenesis of GA (Kaneko et al., Nature 2011). We further identified a new protective role for the enzyme Dicer1 whereby it cleaves Alu RNA transcripts, rendering them innocuous. In GA, the abundance of Dicer1 is reduced which leads to accumulation of cytotoxic Alu RNAs and RPE degeneration. This work was highlighted by commentaries in Cell (2011) and Nature (2011), and will serve as the foundation for the rational design of therapeutics for treating this pervasive disease.
Vascular Heterogeneity in the Eye:
The main goal of the laboratory is to elucidate molecular mechanisms that fundamentally regulate vascular growth in normal and diseased states in the eye. In 2006, we answered the foremost outstanding question in vascular biology: "What is responsible for avascularity of the cornea?" This work (Ambati et al., Nature 2006) demonstrated that, contrary to prevailing dogma that a multitude of anti-angiogenic molecules was required for corneal avascularity, a single protein - soluble VEGF receptor-1 - was uniquely responsible. This work was hailed by Science as a âSignaling Breakthrough of the Yearâ (Adler et al., Science STKE 2007), and is far-reaching because the cornea is the default platform for testing therapies for cancer, atherosclerosis, and other diseases driven by angiogenesis. In 2009 this work was extended to the lymphatic vasculature with our discovery and characterization of a similar, soluble, splice variant of VEGF receptor-2 (Albuquerque et al., Nature Med 2009) which sequesters VEGF-C and is responsible, specifically, for the alymphatic cornea.
Paradigms in Ocular Angiogenesis:
Several corneal and retinal diseases are hallmarked by neovascularization that often leads to irreversible blindness. We seek to identify the specific mediators for such pathologic responses in order to develop targeted therapeutics to reverse and prevent these devastating disorders. Our laboratory was the first to demonstrate the presence of in situ complement activation in the retina and choroid of patients with age-related macular degeneration (AMD). We showed (Nozaki et al., PNAS 2006) that this complement activation triggers the angiogenic switch that transforms the disease state from an atrophic to a neovascular phenotype. This vital observation has now resulted in the initiation of pre-clinical/Phase I clinical trials of complement inhibitors in AMD by more than a dozen pharmaceutical/biotech companies. Crucial to this translational advance was our labâs report of the first animal model of AMD (Ambati et al., Nature Med 2003). This data in conjunction with several other studies has supported a major paradigm shift towards inflammatory and immunologic mediators playing a significant role in the development of AMD and its progression to choroidal neovascularization.
The Interface of Immunity and Vascular Response in the Eye:
How does the omnipresent immune system induce pathologic vascular responses in the eye? Given the fundamental lack of knowledge on the molecular basis of immune regulated angiogenesis, our lab is committed to unraveling these complex biologic interactions. We recently identified (Kleinman et al., Nature 2008) the immune receptor TLR3 as a surprising signaling receptor for small interfering RNAs (siRNAs) in a sequence-independent manner. We showed that siRNAs "generically" suppress angiogenesis in multiple mouse models by activating cell surface TLR3 rather than by triggering RNA interference. These findings, which were covered in commentaries by Nature Medicine (2008) and Nature Biotechnology (2008), advance the nascent understanding of the multifunctional aspects of the immune system within the eye. We will continue our investigations into immunovascular biology with the goal of mapping this critical interface while creating more effective and tolerable medicines to treat neovascular diseases.
Our lab made a major breakthrough in this field by identifying CCR3, a chemokine receptor which has been implicated to be a key player in allergic inflammatory processes, as a biomarker and potential therapeutic target for choroidal neovascularization in age related macular degeneration (Takeda et al., Nature 2009). Of special importance, we were able to detect abnormal blood vessels in vivo in the eyes of mice that spontaneously develop CNV, prior to invasion of the retina, by attaching anti-CCR3 antibodies to tiny semiconductor nanocrystals, or "quantum dots." The discovery of this target may some day enable detection and treatment of neovascular age-related macular degeneration before blood vessels invade the retina and damage eyesight.
Selected Publications
De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, Le O, Beauséjour C, Ambati J, Ambati K, Simon M, Seluanov A, Gorbunova V, Slagboom PE, Helfand SL, Neretti N, Sedivy JM, L1 drives IFN in senescent cells and promotes age-associated inflammation., 2019; Nature. 566(7742) 73-78. PMID: 30728521 | PMCID: PMC6519963
De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, Le O, Beauséjour C, Ambati J, Ambati K, Simon M, Seluanov A, Gorbunova V, Slagboom PE, Helfand SL, Neretti N, Sedivy JM, Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation., 2019; Nature. 572(7767) E5. PMID: 31296937
Al-Khalidi R, Panicucci C, Cox P, Chira N, Róg J, Young CNJ, McGeehan RE, Ambati K, Ambati J, ZabÅocki K, Gazzerro E, Arkle S, Bruno C, Górecki DC, Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism., 2018; Acta neuropathologica communications. 6(1) 27. PMID: 29642926 | PMCID: PMC5896059
Kerur N, Fukuda S, Banerjee D, Kim Y, Fu D, Apicella I, Varshney A, Yasuma R, Fowler BJ, Baghdasaryan E, Marion KM, Huang X, Yasuma T, Hirano Y, Serbulea V, Ambati M, Ambati VL, Kajiwara Y, Ambati K, Hirahara S, Bastos-Carvalho A, Ogura Y, Terasaki H, Oshika T, Kim KB, Hinton DR, Leitinger N, Cambier JC, Buxbaum JD, Kenney MC, Jazwinski SM, Nagai H, Hara I, West AP, Fitzgerald KA, Sadda SR, Gelfand BD, Ambati J, cGAS drives noncanonical-inflammasome activation in age-related macular degeneration., 2017; Nature medicine. () . PMID: 29176737 | PMCID: PMC5760363
Di Ruocco F, Basso V, Rivoire M, Mehlen P, Ambati J, De Falco S, Tarallo V, Alu RNA accumulation induces epithelial-to-mesenchymal transition by modulating miR-566 and is associated with cancer progression., 2017; Oncogene. 37(5) 627-637. PMID: 28991230 | PMCID: PMC5799714
Bogdanovich S, Kim Y, Mizutani T, Yasuma R, Tudisco L, Cicatiello V, Bastos-Carvalho A, Kerur N, Hirano Y, Baffi JZ, Tarallo V, Li S, Yasuma T, Arpitha P, Fowler BJ, Wright CB, Apicella I, Greco A, Brunetti A, Ruvo M, Sandomenico A, Nozaki M, Ijima R, Kaneko H, Ogura Y, Terasaki H, Ambati BK, Leusen JH, Langdon WY, Clark MR, Armour KL, Bruhns P, Verbeek JS, Gelfand BD, De Falco S, Ambati J, Human IgG1 antibodies suppress angiogenesis in a target-independent manner., 2016; Signal transduction and targeted therapy. 1() . PMID: 26918197 | PMCID: PMC4763941
Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, Pittman K, Kubes P, Agarwal HK, Parang K, Hinton DR, Bastos-Carvalho A, Li S, Yasuma T, Mizutani T, Yasuma R, Wright C, Ambati J, Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity., 2014; Science (New York, N.Y.). 346(6212) 1000-3. PMID: 25414314 | PMCID: PMC4274127
Hirano Y, Yasuma T, Mizutani T, Fowler BJ, Tarallo V, Yasuma R, Kim Y, Bastos-Carvalho A, Kerur N, Gelfand BD, Bogdanovich S, He S, Zhang X, Nozaki M, Ijima R, Kaneko H, Ogura Y, Terasaki H, Nagai H, Haro I, Núñez G, Ambati BK, Hinton DR, Ambati J, IL-18 is not therapeutic for neovascular age-related macular degeneration., 2014; Nature medicine. 20(12) 1372-5. PMID: 25473914 | PMCID: PMC4275546
Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, Cho WG, Kaneko H, Fowler BJ, Bogdanovich S, Albuquerque RJ, Hauswirth WW, Chiodo VA, Kugel JF, Goodrich JA, Ponicsan SL, Chaudhuri G, Murphy MP, Dunaief JL, Ambati BK, Ogura Y, Yoo JW, Lee DK, Provost P, Hinton DR, Núñez G, Baffi JZ, Kleinman ME, Ambati J, DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88., 2012; Cell. 149(4) 847-59. PMID: 22541070 | PMCID: PMC3351582
Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, Karikó K, Yoo JW, Lee DK, Hadziahmetovic M, Song Y, Misra S, Chaudhuri G, Buaas FW, Braun RE, Hinton DR, Zhang Q, Grossniklaus HE, Provis JM, Madigan MC, Milam AH, Justice NL, Albuquerque RJ, Blandford AD, Bogdanovich S, Hirano Y, Witta J, Fuchs E, Littman DR, Ambati BK, Rudin CM, Chong MM, Provost P, Kugel JF, Goodrich JA, Dunaief JL, Baffi JZ, Ambati J, DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration., 2011; Nature. 471(7338) 325-30. PMID: 21297615 | PMCID: PMC3077055
Takeda A, Baffi JZ, Kleinman ME, Cho WG, Nozaki M, Yamada K, Kaneko H, Albuquerque RJ, Dridi S, Saito K, Raisler BJ, Budd SJ, Geisen P, Munitz A, Ambati BK, Green MG, Ishibashi T, Wright JD, Humbles AA, Gerard CJ, Ogura Y, Pan Y, Smith JR, Grisanti S, Hartnett ME, Rothenberg ME, Ambati J, CCR3 is a target for age-related macular degeneration diagnosis and therapy., 2009; Nature. 460(7252) 225-30. PMID: 19525930 | PMCID: PMC2712122
Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J, Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth., 2009; Nature medicine. 15(9) 1023-30. PMID: 19668192 | PMCID: PMC2882165
Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Karikó K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J, Sequence- and target-independent angiogenesis suppression by siRNA via TLR3., 2008; Nature. 452(7187) 591-7. PMID: 18368052 | PMCID: PMC2642938
Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJ, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, Mahasreshti PJ, Curiel DT, Kwan D, Marsh H, Ikeda S, Leiper LJ, Collinson JM, Bogdanovich S, Khurana TS, Shibuya M, Baldwin ME, Ferrara N, Gerber HP, De Falco S, Witta J, Baffi JZ, Raisler BJ, Ambati J, Corneal avascularity is due to soluble VEGF receptor-1., 2006; Nature. 443(7114) 993-7. PMID: 17051153 | PMCID: PMC2656128
Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK, An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice., 2003; Nature medicine. 9(11) 1390-7. PMID: 14566334