Xin (Sarah) Zhang, MD
Dr. Zhang's Research Group
941 Stanton L. Young Blvd., BSEB 331A
Oklahoma City, OK 73104-5020
(405) 271-5896 ext 47790
- Roles and mechanisms of endoplasmic reticulum stress in retinal diseases and diabetic complications. The endoplasmic reticulum (ER) is known as the cell’s protein factory where proteins are produced, folded and modified. Only the correctly folded (mature) proteins have biological function and can be used by our body. When the ER homeostasis is disturbed, which can occur in both physiological and disease conditions like nutrient deprivation, hypoxia and viral infection, proteins cannot be properly folded. This will cause the accumulation of misfolded or unfolded proteins in the ER, a condition known as ER stress. These misfolded proteins can aggregate to form insoluble intracellular or extracellular deposit, which is toxic to the cell. It has been demonstrated that many inflammatory disorders, such as diabetes; age-related diseases, such as Alzheimer’s diseases; and neurodegenerative diseases, such as Parkinson’s disease, associate with the build-up of protein aggregate and ER stress. To eliminate the toxic protein components, cells activate an adaptive mechanism known as unfolded protein response (UPR). While transient and low grade ER stress can be overcome by the UPR, persistent or overwhelming ER stress would trigger inflammation and cause cell death. Recently, we have discovered that ER stress play an important role in the pathogenesis of diabetic retinopathy, a common and devastating complication of diabetes in the eye. This disease is a major cause of blindness in the population of working age adults. We have demonstrated that enhancing the function of an adaptive UPR component could protect retinal cells against inflammation and reduce vascular leakage in the retina of diabetic animals. This novel and important finding represents a new mechanism underpinning the pathogenesis of diabetic complications. Our ongoing studies aim to identify the key genes that mediate the cellular damage caused by ER stress and those that initiate the adaptive cascade to protect retinal cells. The ultimate goal is to develop new effective drug therapy to prevent visual impairment caused by retinal diseases and diabetic complications.
- Roles and mechanisms of angiogenic/anti-angiogenic factors in obesity, insulin resistance and Type 2 diabetes. Obesity, insulin resistance and Type 2 diabetes are clustered as the most important metabolic disorders, substantially increasing morbidity and impairing quality of life. Excess body fat mass, particularly visceral fat, leads to the dysregulation of the adipokines (proteins secreted from fat cells) and contributes to increased risk of cardiovascular and peripheral vascular diseases. Recent findings from our group and others indicate that anti-angiogenic factors are associated with obesity and Type 2 diabetes. From bedside to bench, we are investigating the functions and mechanisms of anti-angiogenic inhibitors in lipid metabolism and adiposity using cell culture system and genetic animal models. We recently reported that pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of adipocyte differentiation. PEDF is also involved in regulation of insulin resistance and vascular function in diabetes. Our ongoing studies are focusing on the mechanisms by which PEDF and other angiogenic/anti-angiogenic factors regulate adipogenic signaling pathways and insulin sensitivity. We hope that the outcomes of these studies could provide mechanistic insight and scientific explanations for the clinical observations. In addition, we are collaborating with several clinical investigators inside and outside the University to delineate how these factors are regulated during diabetes and pre-diabetes, and whether the change in their circulation levels can be used as biomarkers for diseases including metabolic syndrome, pre-diabetes, diabetes and peripheral artery disease. We anticipate that these studies will generate important information in identifying new biomarkers and in developing novel therapeutics.
Research in our laboratory is supported by the National Institutes of Health (NIH), the Juvenile Diabetes Research Foundation International (JDRF), American Health Assistance Foundation (AHAF), the Oklahoma Center for the Advancement of Science and Technology (OCAST) and Dr. William Talley Research Award.
||Research fellow, Endocrinology/Cell Biology, University of Oklahoma HSC, Oklahoma City, OK
||Research fellow, Ophthalmology, Medical University of South Carolina, Charleston, SC
||PhD training, Ophthalmology/Pharmacology, Sun Yat-sen University, Guangzhou, China
||MS - Opthalmology, Sun Yat-Sen University of Medical Science, Guangzhou, China
||Clinical fellow, Retina, Zhongshan Ophthalmic Center, Guangzhou, China
||Medical residency, Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China
||MD - Sun Yat-Sen University of Medical Science, Guangzhou, China
Chen YM, Wang JJ, Li J, Ratan R, Townes T and Zhang SX*. Activating transcription factor 4 is a novel regulator of inflammatory genes in diabetic retinopathy. Diabetologia, 2012; DOI 10.1007/s00125-012-2594-1.
Jing G, Wang JJ and Zhang SX*. Endoplasmic reticulum (ER) stress and retinal cell apoptosis. Exp Diabetes Res, 2012; 2012:589589. (Invited review).
Zhong Y, Li J, Wang J, Chen C, Tran JA, Lee A-H, Mandal MN, Le Y-Z and Zhang SX*. Deficiency of X-box binding protein 1 induces oxidative damage of the RPE: implications in age-related retinal degeneration. PlosOne, 2012; 7(6): e38616. doi:10.1371/journal.pone.0038616.
Zhong Y, Wang JJ, Li J, Chen C, Ratan R and Zhang SX*. Activation of Endoplasmic Reticulum Stress by Hyperglycemia is Essential for Inflammatory Cytokine Production in Müller cells in Diabetes. Diabetes, 2012; 61(2):492-504. 2012 Jan 6. [Epub ahead of print].
Zhong Y, Wang JJ and Zhang SX*. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv Exp Med Biol., 2012;723:285-92. NIHMSID: 318185.
Zhang SX, Sanders E, and Wang JJ. Endoplasmic reticulum stress and diabetic retinopathy. J Ocul Biol Dis Infor., (Invited review), 2012, DOI 10.1007/s12177-011-9075-5.
Sunderland KL, Tryggestad JB, Wang JJ, Teague AM, Pratt LV, Zhang SX, Thompson DM, and Short KR. Pigment Epithelium-Derived Factor (PEDF) Varies with Body Composition and Insulin Resistance in Healthy Young People. J Clin Endocrinol Metab., 2012. In press.
Li J, Wang JJ, and Zhang SX (corresponding author). Preconditioning with endoplasmic reticulum stress mitigates retinal endothelial inflammation via activation of X-box binding protein 1. J Biol Chem, 2011, 286(6):4912-21 Epub 2010 Dec 7.
Li J, Wang JJ, Yu Q, Mahadev K, Chen K, and Zhang SX. (Corresponding author). Inhibition of reactive oxygen species by lovastatin down-regulates VEGF expression and ameliorates blood-retinal barrier breakdown in db/db mice: role of NADPH oxidase 4. Diabetes, 2010 Mar 23. [Epub ahead of print].
Li J, Wang JJ, Yu Q, Wang M, Zhang SX. (Corresponding author). Endoplasmic Reticulum Stress is implicated in Retinal Inflammation and Diabetic Retinopathy. FEBS Lett, 2009, 583: 1521-1527.
Wang M, Wang JJ, Li J, Park K, Qian X, Ma J-X, and Zhang SX. (Corresponding author). Pigment Epithelium-derived factor (PEDF) suppresses adipogenesis via inhibition of MAPK/ERK pathway in 3T3-L1 preadipocytes. Am J Physiol Endocrinol. 2009, 297: E1378-87.
Li J, Wang JJ, Yu Q, Mahadev K, Chen K, and Zhang SX. (Corresponding author). Inhibition of reactive oxygen species by lovastatin down-regulates VEGF expression and ameliorates blood-retinal barrier breakdown in db/db mice: role of NADPH oxidase 4. In revision. Diabetes, 2009.
Li J, Wang JJ, Chen D, Mott R, Yu Q, Ma J-X, and Zhang SX. Systemic Administration of HMG CoA Reductase Inhibitor Protects the Blood-retinal Barrier and Ameliorates Retinal Inflammation in Type 2 diabetes. Experimental Eye Research 2009 Feb 28 89(1): 71-78. [Epub ahead of print].
Yu Y, Jenkins AJ, Nankervis AJ, Hanssen K, Scholz H, Henriksen T, Lorentzen B, Garg SK, Menard MK, Hammad S, Scardo JC, Stanley JR, Dashti A, May K, Lu K, Aston CE, Zhang SX, Ma J-x, and Lyons TJ. Anti-angiogenic factors and preeclampsia in Type 1 diabetes. Diabetologia 52:160-168, 2009.
Zhang SX, Wang JJ, Dashiti A, Wilson K, Zou M-H, Szweda L, Ma J-x, and Lyons TJ. Pigment Epithelium-derived Factor (PEDF) mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized-LDL. J Mol Endocrinol, June 27, 2008 [Epub ahead of print].
Zhang SX, Wang JJ, Mott R, Chen Y, Knapp RR, Cao W, and Ma J-x. Anti-inflammatory Effects of Pigment Epithelium-derived Factor in Diabetic Nephropathy. Am J Physiol Renal Physiol, [Epub ahead of print], 2008.
Zhang SX, Jenkins AJ, Rowley KG, Karschimkus CS, Nelson CL, Lyons TJ, Best JD, and Ma J-x. Increased Serum PEDF is Associated With Microvascular Complications, Vascular Stiffness, and Inflammation in Type 1 Diabetes. Diabet. Med, 24: 1345-1351, 2007.
Zhang SX, and Ma J-x. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res, 26(1):1-37, 2007.
Zhang SX, Wang JJ, Gao G, Park K, and Ma, J-x. Reciprocal regulation between pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF). J. Mol. Endocrinol., 37(1):1-12, 2006.
Sima J, Ma J-x, Zhang SX, Guo J. Study of the influence of angiostatin intravitreal injection on vascular leakage in retina and iris of the experimental diabetic rats.
Yan Ke Xue Bao. 22(4):252-8, 2006.
Tomasek JJ, Haaksma CJ, Schwartz RJ, Vuong DT, Zhang SX, Ash JD, Ma J-x, Al-Ubaidi MR. Deletion of smooth muscle α-actin alters blood-retina barrier permeability and retinal function. Invest Ophthalmol Vis Sci., 47(6):2693-2700, 2006.
Zhang SX, Wang JJ, Mott R, Knapp RR, Cao W, Lau K, and Ma J-x. Salutary Effect of Pigment Epithelium-Derived Factor in Diabetic Nephropathy: Evidence for Anti-fibrogenic Activities. Diabetes, 55(6):1678-1685, 2006.
Liu L, Yu Q, Wang H, Zhang SX, Huang C, and Chen X. Association of Intercellular Adhesion Molecule 1 Polymorphisms with Retinopathy in Chinese Patients with Type 2 Diabetes. Diabet. Med., 23: 643-648, 2006.
Zhang SX, Wang JJ, Lu K, Mott R, and Ma J-x. Therapeutic Potential of Angiostatin in Diabetic Nephropathy. J. Am. Soc. Nephro., 17(2):475-486, 2006.
Zhang SX, Wang JJ, Lu K, Mott R, and Ma J-x. Pigment Epithelium-derived Factor (PEDF) Is A Novel Endogenous Anti-inflammatory Factor. FASEB J., 20(2):323-325, 2006.
Zhang SX, Ma J-x, Sima J, Ottlecz A, Hu M, Lambrou GN. Genetic Difference in Susceptibility to the Blood-retina Barrier Breakdown in Diabetes and Oxygen-induced Retinopathy. Am.J.Pathol., 166: 313-321, 2005.
Zhang SX, Sima J, Wang JJ, Shao C, Fant J, and Ma J-x. Systemic and periocular delivery of plaseminogen kringle 5 reduces vascular leakage in rat models of oxygen-induced retinopathy and diabetes. Curr. Eye Res., 30:681-689, 2005.
Zhang SX, Wang J, Lu K, Chen Y, Mott R, Sato S, and Ma J-x. Decreased Expression of Pigment Epithelium-derived Factor Is Involved in the Pathogenesis of Diabetic Nephropathy. Diabetes, 54: 243-250, 2005.
Reviews and Invited Papers
Zhang SX, and Ma J-X. Ocular Neovascularization: Implication of Endogenous Angiogenic Inhibitors and Potential Therapy. Prog Retin Eye Res, 26(1):1-37, 2007.
Ma J-x, Zhang SX, Wang JJ. Down-regulation of Angiogenic Inhibitors: A New Pathogenic Mechanism For Diabetic Complications. Invited Review Curr Diabetes Rev. 1, 183-196, 2005.
Books Chapters and Manuscripts
Ma J-X, Zhang SX. Endogenous Angiogenic Inhibitors in Diabetic Retinopathy. in "Ocular Angiogenesis: Diseases, Mechanisms and Therapeutics" Eds J. Tombran-Tink and CJ Barnstable, Humana Press, Totowa, NJ. 2006, pp 23-44.