Gender	Male
E-mail	zhongmin.ma@mssm.edu
Education and Training	Ph.D., St. Louis University School of Medicine

Education and Training	Ph.D., St. Louis University School of Medicine

Research

Specific Clinical/Research Interest:
Phospholipid signaling in pancreatic beta-cell function, apoptosis, and regeneration; Autoimmunity; cell membrane homeostasis and cell cycle checkpoint regulation; Autophagy and iron metabolism in brain

Postdoctoral Fellows: Xu Zhang, Zhengshan Zhao, Konstantin Seleznev
Research Personnel: Research Assistant: Chunying Zhao

Summary of Research Studies:
Dysfunction and death of pancreatic beta cells play a central role in the pathogenesis of diabetes, one of the most prevalent diseases in the world. The primary goal of this laboratory is to understand the role of Ca2+-independent phospholipase A2 (iPLA2)-mediated pathway in insulin secretion and beta cell expansion and death. iPLA2 catalyzes the hydrolysis of the sn-2 fatty acyl bond of phospholipids to liberate free fatty acids such as arachidonic acid, an important precursor for synthesis of eicosanoids, and lysophospholipids such as lysophosphatidylcholine, a precursor of platelet-activating factor and regulates membrane phospholipid homeostasis. iPLA2 expression in diabetic animal models such as NOD and db/db mice is down-regulated. Recently, it was discovered that mutations in iPLA2 gene, PLA2G6, underlie infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) and the related Karak syndrome. These findings highlight an importan! t role of iPLA2 in the pathogenesis of these diseases. iPLA2 contains several functional domains including an ankyrin repeat domain, an ATP-binding domain, a bipartite nuclear localization signal, a proline rich region, a calmodulin-binding domain, and several caspase 3 cleavage sites, which may be involved in its regulation and localization under different physiological and pathological conditions. We apply molecular, proteomic, and lipidomic techniques to study the function of iPLA2 in cells and use siRNA silencing, gene knockout, and transgenic animal models to study its physiological role in vivo. Under physiologic condition, pancreatic islets secrete insulin and release arachidonic acid in response to glucose stimulation. We found that inhibition of iPLA2 in mice results in insufficient insulin secretion and impaired glucose tolerance. Interestingly, iPLA2 contains an ATP binding domain and its activity is stimulated several fold by ATP in beta cells. One of our projects is to understand its regulation in glucose-stimulated insulin secretion. Phospholipids are the major building blocks of cell membranes, which are crucial to the life of the cell. We found that inhibition of iPLA2 activates the p53-p21cip1 checkpoint mechanism thereby blocking the entry of G1 cells into S phase. Our second project is to characterize the molecular mechanism by which inhibition of iPLA2 activates p53 checkpoint. Mitochondrial phospholipid cardiolipin molecules play a key role in mitochondrial function. Because of its rich in polyunsaturated fatty acids, cardiolipin is the main target of reactive oxygen species (ROS). Under physiological conditions, mitochondria can repair peroxidative damage of cardiolipin through a r emodeling mechanism via the deacylation-reacylation cycle mediated by PLA2 and acyl-coenzyme A-dependent monolysocardiolipin acyltransferase. We found that iPLA2 protects mitochondrial function from damage caused by mitochondrially generated ROS during apoptotic induction. Our third project is to elucidate the iPLA2-mediated cardiolipin remodeling in beta cell mitochondria. iPLA2 also plays a critical role in clearance of apoptotic cells. Failure to clear apoptotic cells promptly has serious consequence for inflammation and autoimmunity. iPLA2 contains a caspase 3-cleavage site and its activation is associated with release of recruitment signal LPC for phagocyte attraction. One of our projects is to investigate its role in triggering autoimmunity during the development of type 1 diabetes.

Zhang XH, Zhao C, Ma ZA. Increase of Phosphatidylcholines Containing Polyunsaturated Fatty Acids in Cell Membrane Induces Phosphorylation of p53 by Activating ATR. J Cell Sci ; 120.

Seleznev K, Zhao C, Ma ZA, Song K, Zhang XH. Calcium-independent Phospholipase A2 Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine. J Biol Chem 2006; 281: 22275-22288.

Zhang XH, Zhao C, Ma ZA, Song K, Manfredi JJ, Seleznev K. Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase. J Cell Sci 2006; 119: 1005-1015.

Song K, Zhang X, Ma Z, Ang NT, Zhao C. Inhibition of Ca2+-independent Phospholipase A2 Results in Insufficient Insulin Secretion and Impaired Glucose Tolerance. Mol Endocrinol 2005; 19: 504-515.

Wang Z, Ramanadham S, Ma ZA, Turk J, Mancuso DJ, Gross RW, Bao S. Group VIA Phospholipase A2 Forms a Signaling Complex with the Calcium/Calmodulin-dependent Protein Kinase IIb Expressed in Pancreatic Islet b-Cells. J Biol Chem 2005; 280: 6840-6849.

Bao S, Miller DJ, Ma Z, Turk J, Eng G, Ramanadham S, Moley K, Wohltmann M. Male Mice That Do Not Express Group VIA Phospholipase A2 Produce Spermatozoa with Impaired Motility and Have Greatly Reduced Fertility. J Biol Chem 2004; 279: 38194-38200.