Jian-Xing Ma M.D. Ph.D.

Appointments:

Laureate Professor and Chairman 

Special lnterests:

  • Angiogenesis and inflammation in diabetic complications 
  • Vitamin A metabolism and retinal neurodegeneration 

Training:

  • M.D. Jiangxi Medical College, China 
  • M.S. Chinese Academy of Medical Sciences, Beijing, China 
  • Ph.D. Medical University of South Carolina, Charleston, SC 

Research Summary:

1. Vitamin A metabolism and retinal degeneration: Vitamin A is essential for vision. However, vitamin A is all-trans retinol which needs to be converted to 11-cis isoforms to be used for vision. Retinal isomerohydrolase is a key enzyme for generating 11-cis retinal, the chromophore for visual pigment, from vitamin A. My group is the first who showed direct evidence indicating that RPE65 is the isomerohydrolase. Further, we found that RPE65 is an iron-binding protein. The identification of the function of RPE65 opened a new era for the investigation of retinal dystrophies caused by RPE65 mutations in patients. Currently, we are studying the mechanism of this unique and important enzyme and investigating how mutations in this enzyme cause retinal degeneration. 

2. Oxidative stress and inflammation in diabetic microvascular complications and age-related-macular degeneration (AMD): Diabetic retinopathy is a major microvascular complication of diabetes. AMD is a leading cause of blindness. Oxidative stress, inflammation and vascular dysfunctions such as vascular leakage are known to play important roles in these disorders. Currently, there is no satisfactory treatment, as their pathogenesis is uncertain. Recently, we have reported that the Wnt pathway activation is responsible, at least in part, for these microvascular complications in diabetic retinopathy and AMD. We are studying the mechanism for the Wnt pathway activation in these diseases. The goal of this research is to identify novel therapeutic targets for these diseases.

3. Endogenous angiogenic inhibitors, pathological angiogenesis, inflammation and vascular leakage in diabetes: Pathological angiogenesis (neovascularization), inflammation and vascular leakage are common features of diabetic vascular complications and other diseases such as age-related macular degeneration, cancer, infections and glaucoma. We have identified several peptide angiogenic inhibitors endogenously expressed in ocular and vascular tissues. We have shown that decreased levels of these inhibitors are associated with inflammation, fibrosis, vascular leakage and neovascularization in diabetic retina and kidney. Our recent experiments showed that these peptides inhibit inflammation in diabetic retina, protect blood-retinal barrier, reduce vascular leakage and inhibit retinal neovascularization in diabetic retinopathy animal models. Moreover, we have shown that these angiogenic inhibitors also inhibit inflammation and fibrosis in diabetic kidney and significantly reduce proteinuria in a diabetic rat model. We are using molecular biology and physiology methods to study the molecular mechanisms underlying the vascular activities of these peptides and their physiological functions. We will also explore the therapeutic potential of these peptides in diabetic complications. The long-term goal is to develop a new, non-invasive therapy using these natural peptides to block neovascularization and vascular leakage in diabetic complications.

Relevant Publications:

  1. Ma, J-x, Znoiko, S., Othersen, K.L., Ryan, J.C., Das, J., Isayama, T., Kono, M., Oprian, D.D., Corson, D.W., Cornwall, C., Makino C. and Crouch, R.K. (2001) A visual pigment expressed in both rod and cone photoreceptors. Neuron, 32, 451-461.
  2. Moiseyev, G., Chen, Y., Takahashi, Y. and Ma, J-x. (2005) RPE65 is the isomerohydrolase in the visual cycle. Proc. Natl. Acad. Sci. USA, 102, 12413-12418.
  3. Zhang, S.X., Wang, J.J., Lu, K. Mott, R. and Ma, J-x. (2006) Therapeutic potential of angiostatin in diabetic nephropathy. J. Am. Soc. Nephrol., 17, 475-486.
  4. Zhang B, Abreu JG, Zhou KK, Chen Y, Hu Y, Zhou T, He X, and Ma J-x (2010) Blocking the Wnt Pathway, a Unifying Mechanism for an Angiogenic Inhibitor in the Serine Proteinase Inhibitor Family. Proc. Natl. Acad. Sci. USA. 107, 6900-6905. PMCID: PMC2872418
  5. Moiseyev, G., Nikolaeva, O., Chen, Y., Farjo, K., Takahashi, Y. and Ma, J-x. (2010)Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt's disease. Proc. Natl. Acad. Sci. USA., 107, 17551-17556. PMCID:PMC2955102
  6. Liu, Q., Li, J., Cheng, R., Chen, Y., Lee, K., Hu, Y., Yi, J., Liu, Z., and Ma, J-x. (2013) Nitrosative stress plays an important role in Wnt pathway activation in diabetic retinopathy. Antioxidants & Redox Signaling, 18(10):1141-53. PMCID:PMC3579458
  7. Hu, Y., Chen, Y., Ding, L., He, X., Takahashi, Y., Gao, Y., Shen, W., Cheng, R., Chen, Q. and Ma, J-x (2013) Pathogenic role of the diabetes-induced PPAR-αlpha down-regulation in microvascular dysfunction. Proc. Natl. Acad. Sci. USA., 110, 15401-15405. PMCID:PMC3780907
  8. McBride, J., Alicia Jenkins, A.J., Liu, X., Zhang, B., Lee, L., Berry, W.L., Janknecht, R., Griffin, C., Aston, C.E., Lyons, T., James J. Tomasek, J.J. and Ma, J-x. (2014) Elevated Circulation Levels of an Anti-angiogenic SERPIN Impairs Wound Healing through Suppression of Wnt Signaling. J. Invest. Dermatol., 134:1725-34. PMID:24463424
  9. Takahashi, Y., Moiseyev, G. and Ma, J-x. (2014) Identification of Key Residues Determining Isomerohydrolase Activity of Human RPE65. J. Biol. Chem. 289(39):26743-51. PMCID:PMC4175317
  10. Chang, B., Tessneer, K., McManus, J., Liu, X., Hahn, S., Pasula, S., Wu, H, Song, S., Chen, Y., Cai, X., Dong, Y., Brophy, M., Rahman, R., Ma, J-x., Xia, L. and Chen, H. (2015) Epsin is required for Dishevelled stability and Wnt signaling activation in colon cancer development. Nature Communication. 6:6380. PMCID: PMC4397653.
  11. Chen, Q., Takahashi, Y., Oka, K., and Ma, J-x. (2016) Functional Differences of Very-Low-Density Lipoprotein Receptor Splice Variants in Regulating Wnt Signaling. Mol. Cell. Biol. 36, 2645-54. PMCID:PMC5038150
  12. Cheng, R., Ding, L., He, X., Takahashi, Y., and Ma, J-x. (2016) Interaction of PPARalpha with the canonic Wnt pathway in the regulation of renal fibrosis. Diabetes, 65(12):3730-3743. PMCID:PMC5127249
  13. He, X., Cheng, R., Park, K., Benyajati, S., Moiseyev, G., Sun, C., Olson, L., Yang, Y., Eby, B.K., Lau, K., and Ma, J-x. (2016) Pigment epithelium-derived factor alleviates renal tubulointerstitial fibrosis and protects renal proximal tubule epithelial cells via inhibition of the Wnt pathway. Kidney International, S0085-2538(16)30588-9. PMID:27914705
  14. Shin, Y., Moiseyev, G., Charkraborty, D. and Ma, J-x. (2017) A dominant mutation in Rpe65, D477G, delays dark-adaptation and disturbs the visual cycle in the mutant knock-in mice. Am. J. Pathol. 187(3):517-527. PMCID:PMC5389371
  15. Chen, Q., Qiu, F., Zhou, K. Matlock, H.G., Takahashi, Y., Rajala, R.V.S., Yang, Y., Moran, E. and Ma.J-x. (2017) Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα. Diabetes, 66:1671-1682. PMCID: PMC5440012
  16. Malechka, V.V., Moiseyev, G., Takahashi, Y. Shin, Y. and Ma, J-x. (2017) Impaired Rhodopsin Generation in the Rat Model of Diabetic Retinopathy. Am. J. Pathol. 187:2222-31. PMID:28734946. PMID:28734946
  17. Pearsall E, Cheng R, Zhou K, Takahashi Y, Matlock G, Vadvalkar S, Shin Y, Fredric TW, Gantner ML, Meng S, Fu Z, Gong Y, Kinter M, Humphries KM, Szweda L, Smith L and Ma J-x. (2017) PPARα is Essential for Retinal Lipid Metabolism and Neuronal Survival. BMC Biology. 15(1):113, doi: 10.1186/s12915-017-0451-x. PMCID:PMC5706156

Funding Agencies:

NIH R01 EY019309 Ma (PI) 03/01/18 to 02/29/22 

NIH R01 EY018659 Ma (PI) 06/1/15 to 05/31/20

OCAST HR16-041 Ma (PI) 10/01/16 – 09/30/19

NIH P30 GM122744 Ma (PI) 07/01/17 to 06/30/22

NIH R01EY12231 Ma and Moiseyev (MPI) 09/30/18 to 08/31/22

NIH R01EY028949 Karamichos and Ma (MPI) 09/01/18 to 08/31/21

Contact:

Office telephone: (405) 271-4372 
Email: jian-xing-ma@ouhsc.edu