Jiyang Cai, PhD

Assistant Professor, UTMB Department of Ophthalmology & Visual Sciences

Email: jicai@utmb.edu

Jiyang Cai received his Ph.D. from Emory University where he majored in Molecular Therapeutics and Toxicology. He did his postdoctoral training at Yale Cancer Center with Dr. Alan Sartorelli. Prior to joining the UTMB Department of Ophthalmology and Visual Sciences in 2012, he worked as an assistant professor at the Vanderbilt Eye Institute in Nashville, TN. As an independent investigator, Dr. Cai has published more than 40 peer-reviewed papers and has been awarded a number of grants from the National Institutes of Health and various private foundations.

Dr. Cai's research program is on mechanisms of aging and age-related degeneration in the retinal pigment epithelium (RPE). The RPE is a single layer of epithelial cells lined between the neurosensory retina and choriocapillaris. It is part of the blood-retina barrier and is highly active in visual cycle-related metabolic functions. Degeneration of the RPE with aging is an initiating event in age-related macular degeneration (AMD) and oxidative stress is considered as a major environmental risk factor of AMD.

1. Rodent model related to AMD

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant and detoxification responses. Elevating the transcriptional activity of Nrf2 can protect against oxidative injury to the RPE. Dr. Zhenyang Zhao in our lab has shown that mice deficient of Nrf2 developed pathological features similar to human AMD. Nrf2 knockout (Nrf2-/-) mice developed age-dependent RPE/choroid degeneration, spontaneous CNV and deposits of complement-related proteins in the sub-RPE space. Each of these features is observed in human AMD eyes, suggesting that the Nrf2-/- mouse is a useful tool for probing specific aspects of disease initiation and progression. One of our ongoing projects is to further optimize this model with environmental conditions that can potentially accelerate the degenerative processes.

2. Autologous transplant of RPE derived from IPSCs

The majority of AMD patients have the atrophic or dry form of the disease, which is resulted from degeneration of the RPE and loss of photoreceptor cells in the central retina. Currently there is no cure for dry AMD. Similar to neurons, RPE cells usually do not replicate in vivo and will lose their function and viability during aging and age-related degeneration. Regenerative medicine using stem cell-derived RPE is an emerging new therapy and has entered the early phase of clinical trials. The project's long-term objective is to produce patient-specific pluripotent stem cells to accelerate the implementation of stem cell therapy for degenerative disorders of the eye. In collaboration with investigators at the University of Pennsylvania, we will generate inducible pluripotent stem cells (iPSCs) from adult mouse tail-tip fibroblasts using a virus-free transposon system and differentiate them into RPE cells in vitro. The RPE cells will be transplanted to Nrf2 knockout mice for characterization of the long-term survival and function.

3. Exosomal microRNA from the RPE

Exosomes are extracellular membranous vesicles that are generated from intracellular multivesicular bodies (MVBs). They contain messenger RNAs (mRNAs) and microRNAs (miRNAs) that can be transferred from producer cells to recipient cells. The goal of this project is to characterize exosomes shuttle RNA as a potentially novel signaling mechanism between the RPE and choroidal endothelial cells (CECs).

Publications

A. Articles in Peer-Reviewed Journals

1. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997;275:1129-1132.

2. Cai J, Jones DP. Superoxide in apoptosis: mitochondrial generation triggered by cytochrome c loss. J Biol Chem. 1998;273:11401-11404.

3. Samal A, Cai J, Zhivotovsky B, Jones DP, Orrenius S. Presence of a pre-apoptotic complex of pro-caspase-3, Hsp 60 and Hsp 10 in the mitochondrial fraction of Jurkat cells. EMBO J. 1999;18:2040-2048.

4. Nelson KC, Carlson J, Newman ML, Sternberg P Jr, Jones DP, Kavanagh TJ, Diaz D, Cai J, Wu M. Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40:1927-1935.

5. Cai J, Wu M, Nelson K, Sternberg P Jr, Jones DP. Oxidant induced apoptosis in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40:959-966.

6. Kirlin WG, Cai J, Delong MJ, Pattern EJ, Jones DP. Cancer preventive phase 2 enzyme inducers activate cell death in HT 29 colon carcinoma cells. J Nutri. 1999;129:1827-1835.

7. Jiang S, Cai J, Wallace DC, Jones DP. Cytochrome c-mediated apoptosis in cells lacking mitochondrial DNA: signaling pathway involving release and caspase 3 activation is conserved. J Biol Chem. 1999;274:29905-29911.

8. Kirlin WG, Cai J, Thompson SA, Diaz D, Kavanagh TJ, Jones DP. Glutathione Redox Potential during Differentiation and Enzyme Induction. Free Radic Biol Med. 2000;27:1208-1218.

9. Jones DP, Carlson JL, Mody VC, Cai J, Lynn MJ, Sternberg P Jr. Redox state of glutathione in human plasma. Free Radic Biol Med. 2000;28:625-635.

10. Cai J, Wallace DC, Zhivotosky B, Jones DP. Separation of cytochrome c-dependent caspase activation from thiol-disulfide redox change in cells lacking mitochondrial DNA. Free Radic Biol Med. 2000;29:334-342.

11. Chen Y, Cai J, Anders MW, Stevens J, Jones DP. Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced apoptosis. Toxicol Appl Pharmacol. 2001;170:172-180.

12. Chen Y, Cai J, Murphey TJ, Jones DP. Overexpressed human mitochondrial thioredoxin confers resistance to oxidant-induced apoptosis in human osteosarcoma cells. J Biol Chem. 2002;277:33242-33246.

13. Nelson KC, Armstrong JS, Moriarty S, Cai J, Wu MH, Sternberg P Jr, Jones DP. Oltipraz, a cancer chemopreventive agent, protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci. 2002;43:3550-3554.

14. Cai J, Chen Y, Seth S, Frukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med. 2003;34:928-936.

15. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC. ANTs are not essential elements of the mitochondrial PT pore, but are required for its regulation. Nature 2004;427:461-465.

16. Cai J, Chen Y, Murphy TJ, Jones DP, Sartorelli AC. Role of caspase activation in butyrate-induced terminal differentiation in HT 29 clon carcinoma cells. Arch Biochem Biophys. 2004;424:119-127.

17. Adams BK, Cai J, Armstrong J, Herold M, Snyder JP, Liotta DC, Jones DP, Shoji M. EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. Anticancer Drug 2005;16:263-275.

18. Jiang S, Moriarty-Craige SE, Orr M, Cai J, Sternberg P Jr, Jones DP. Oxidant-induced apoptosis in human retinal pigment epithelial cells: dependence on extracellular redox state. Invest Ophthalmol Vis Sci. 2005;46:1054-1061.

19. Ha N, Chen Y, Cai J, Sternberg P Jr. Increased Glutathione Synthesis through an ARE-Nrf2 Dependent Pathway by Zinc in the RPE: Implication for Protection against Oxidative Stress. Invest Ophthalmol Vis Sci. 2006;47:2709-2715.

20. Chen Y, Kirlin WG, Jones DP, Sartorelli AC, Cai J. Overexpression of heat shock factor 1 inhibits butyrate-induced differentiation in colon cancer cells. Cell Stress Chaperones. 2006;11:199-207.

21. Chen Y, Yu M, Greenamyre JT, Jones DP, Cai J. Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells. Toxicol Appl Pharmacol. 2006;216:256-262.

22. Chen Y, Jones DP, Cai J. Redox regulation of oxidant-induced cell death, the role of mitochondrial thioredoxin. FEBS Lett. 2006;580:6596-6602.

23. Jiang G, Tidwell K, McLaughlin BA, Cai J, Gupta RC, Milatovic D, Nass R, Aschner M. Neurotoxic potential of depleted uranium-effects in primary cortical neuron cultures and in Caenorhabditis elegans. Toxicol Sci. 2007;99:553-565.

24. Jiang S, Moriarty-Craige SE, Lynn M, Li C, Cai J, Jones DP, Sternberg P. Association of plasma soluble Fas ligand with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49:1345-1349.

25. Rezaei KA., Chen Y, Cai J, Sternberg P. Zip2, a zinc transporter protein, modulates Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol Vis Sci. 2008;49:1665-1670.

26. Wang L, Chen Y, Sternberg P, Cai J. Essential Roles of the PI3 kinase/Akt pathway in Regulating Nrf2-dependent Antioxidant Functions in the RPE. Invest Ophthalmol Vis Sci. 2008;49:1671-1678.

27. Chen Y, Sternberg P, Cai J. Characterization of a Bcl-XL interacting protein,FKBP8 and its splicing variant in human RPE cells. Invest Ophthalmol Vis Sci. 2008;49:1721-1727.

28. Chen Y, Go YM, Jones DP, Cai J. Increased mitochondrial thioredoxin potentiate N-ethylmaleimide-induced cytotoxicity. Chem Res Toxicol. 2008;21:1205-1210.

29. He M, Cai J, Go YM, Johnson JM, Martin WD, Hansen JM, Jones DP. Identification of thioredoxin-2 as a regulator of the mitochondrial permeability transition. Toxicol Sci. 2008;105:44-50.

30. Wang L, Jiang HY, Aschner M, Cai J. Nrf2-dependent antioxidant system and methylmercury toxicity in astrocytes. Toxicol Sci. 2009;107:135-143.

31. Chen J, Wang L, Chen Y, Sternberg P, Cai J. Phosphatidylinositol 3 kinase pathway controls 4-hydryoxy-2-nonenal-induced oxidative injury in the RPE. Invest Ophthalmol Vis Sci. 2009;50:936-942.

32. Ni M, Li X, Yin Z, Jiang H, Sidoryk-Wgrzynowicz M, Milatovic D, Cai J and Aschner M. Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicol Sci. 2010;116:590-603.

33. Chen Y, Wang J, Cai J and Sternberg P. Altered mTOR Signaling in Senescent Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2010;51:5314-5319.

34. Rezaei KA, Toma HS, Cai J, Penn JS, Sternberg P and Kim SJ. Reduced choroidal neovascular membrane formation in cyclooxygenase-2 null mice. Invest. Ophthalmol. Vis. Sci. 2011;52:701-707.

35. Stankowski JN, Zeiger SL, Cohen EL, DeFranco DB, Cai J and McLaughlin BM. C-terminus of HSC70 interacting protein increases following stroke and impairs survival against acute oxidative stress. Antioxidant Redox Signaling 2011;14:1787-1801.

36. Zhao ZY, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE and Cai J. Age-related retinopathy in Nrf2-deficient mice. PLoS One 2011;6:e19456

37. Brantley MA, Osborn MP, Sanders BJ, Rezaei KA, Lu P, Li C, Milne GL, Cai J and Sternberg P. Plasma biomarkers of oxidative stress and genetic variants in age-related macular degeneration. Am J Ophthalmol 2012;153:460-467.

38. Brantley MA, Osborn MP, Sanders BJ, Rezaei KA, Lu P, Li C, Milne GL, Cai J and Sternberg P. The short term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: a pilot investigation. Am J Ophthalmol 2012;153:1104-1109.

39. Jiang T, Chang Q, Zhao Z, Yan S, Wang L, Cai J and Xu G. Melatonin-mediated cytoprotection against hyperglycemic injury in Muller cells. PLoS One 2012;7:e50661.

40. Han W, Li H, Cai J, Gleaves LA, Polosukhin W, Segal BH, Yull FE and Blackwell TS. NADPH oxidase limits lipopolysaccharide-induced lung inflammation and injury in mice through reduction-oxidation regulation of NFkB activity. J. Immunol. 2013;190,4786-4794

B. Reviews and Book Chapters

1. Cai J, Yang J, Jones DP. Mitochondrial control of apoptosis: the role of cytochrome c. Biochem Biophys Acta. 1998;1366:139-150.

2. Cai J, Jones DP. Mitochondrial redox signaling during apoptosis. J Bioenerg Biomem. 1999;31:327-334.

3. Cai J, Nelson K, Wu M, Jones DP, Sternberg P Jr. Oxidative damage and protection of the RPE. Prog Retin Eye Res. 2000;19:201-225.

4. Waston B, Cai J, Jones DP. Diet and Apoptosis. Ann Rev Nutri. 2000;20:485-505.

5. Cai J, Sternberg P, Jones DP. (2002) Oxidative stress and age-related macular degeneration. In: Culter R.G. and Rodriguez, H. eds Oxidative Stress and Aging: advances in basic science, diagnostics and intervention. World Scientific. p 987-998.

6. Jiang S, Cai J, Jones DP, Sternberg P. (2008) Plasma soluble Fas ligand and age-related macular degeneration. In: US Ophthalmic Review (Volume 3) p 62-65.

7. Chen Y, Zhao ZY, Sternberg P and Cai J*. (2012) NRF2 and age-related RPE degeneration. InTech - Open Access Publisher. ISBN 979-953-51-0248-9 pp 427-450

8. Brantley MA, Osborn MP, Cai J, Sternberg P. (2012) Oxidative stress and systemic changes in age-related macular degeneration. In: Stratton RD, Hauswirth WW and Gardner TW. eds Oxidative Stress in Applied Basic Research and Clinical Practice: studies on Retinal and Choroidal Disorders. Humana Press p367-399. ISBN 978-1-61779-605-0