|B.S., 1986, University of Michigan |
|Ph.D., 1992, University of Michigan |
|Postdoctoral, 1992-1997, Washington University School of Medicine in St. Louis |
|Research Instructor, 1998-2005, Washington University School of Medicine in St. Louis |
My long-term research interests are to understand the mechanisms involved in the regulation of ß-cell proliferation and survival, which may provide potential strategies to modulate ß-cell mass in diabetic patients to prevent or reverse type 1 and type 2 diabetes. Lipotoxicity (toxic effects of lipids) is believed to be one of the major factors that contribute to defects in insulin secretion and ß-cell death. Increased levels of FFA in the circulation of obese subjects facilitate deposit of lipid molecules in all tissues including ß-cells. FFA taken up by ß-cells undergoes either mitochondria-mediated ß-oxidation (metabolism) or conversion into neutral lipid, primarily triglyceride (TG). Neutral lipid is stored in lipid vesicles in the cytosol. The structure of lipid vesicles contains a large core of neutral lipids covered by a phospholipid monolayer. Recent studies have shown that the surface of lipid vesicles is coated with a family of proteins including perilipin, adipose differentiation-related protein (ADRP), S3-12, and TIP47. These lipid vesicle-associated proteins are postulated to provide a protective mechanism from lipotoxicity by containing neutral lipids in the lipid vesicles. It is generally believed that FFAs in the cytosol rather than neutral lipids in the lipid vesicles are the cause of lipotoxicity.
My previous research indicates that both primary and tumor cell lines of ß-cells express ADRP, which appears to be the predominant lipid vesicle-associated protein in the ß-cell. I postulate that ADRP plays a key role in protecting ß-cells from lipotoxicity associated with obesity-mediated type 2 diabetes. I hypothesize if the flux of FFAs into the ß-cells exceeds the capacity of ADRP to contain them in lipid vesicles in the form of TG, the spill over of FFAs into the cytosol causes ß-cell lipotoxicity. One of my research projects is to test this hypothesis by knocking out the ADRP gene in INS-1, a rat insulinoma cell line, using small interfering RNA (siRNA). siRNA technology is a new revolutionizing tool to specifically knock-out a gene's message, and subsequently the protein level of the targeted gene, providing a means to study the function of a specific protein. If my hypothesis is correct, increased susceptibility of ß-cells to FFA-mediated lipotoxicity is anticipated when the expression of the ADRP gene is significantly reduced. Understanding specific mechanisms involved in the ß-cell lipotoxicity may provide strategies to intervene this process that leads to the development of obesity-mediated type 2 diabetes.
My other research projects involve understanding the mechanisms involved in the ß-cell growth and proliferation, focusing on various signaling cascades that activate mammalian target of rapamycin (mTOR), a serine and threonine kinase, that plays a role as a nutrient sensor. The ability to maintain ß-cell mass is a key whether overt diabetes occurs or not, in spite of obesity and peripheral insulin resistance. Elucidation of the mechanisms involved in the ß-cell growth, proliferation, and various inputs that affect ß-cell mass is essential to provide strategies to protect ß-cells and prevent the development of type 2 diabetes.
My lab is a newly built state-of-art modern lab equipped with a complete cell culture facility and other equipment for research on cellular and molecular biology. Some of the equipment includes cell culture hood, incubator, various centrifuges, water bath, fluorescent plate reader, inverted fluorescent microscope with an intelligent automation system, small and large gel apparatus, and numerous other small equipment. Other equipment available in the School of Pharmacy include real time quantitative RT-PCR machine, UV/visible spectrophotometer, digital gel documentation system, lyophilizer, shaker incubators, speed vacuum concentrator, trans-illuminator, conductivity probe, hot plate/stirrer, laser light scattering analyzer, untrasonic bath, ice machine, autoclave, various refrigerators and freezers.
1. Xu, G., Kwon, G., Cruz, W. S., Marshall, C. A., McDaniel, M. L. (2001) Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes 50: 353-360
2. McDaniel, M. L., Marshall, C. A., Pappan, K. L., Kwon, G. (2002) Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic ß-cells. Diabetes 51: 2877-2885
3. Kwon, G., Pappan, K. L., Marshall, C. A., Schaffer, J. E., McDaniel, M. L. (2004) cAMP dose-dependently prevents palmitate-induced apoptosis by both protein kinase A- and cAMP-guanine nucleotide exchange factor-dependent pathways in ß-cells. J. Biol. Chem. 279: 8938-8945
4. Kwon, G., Marshall, C. A., Pappan, K. L., Remedi, M. S., McDaniel, M. L. (2004) Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. Diabetes 53 Suppl 3: 5225-5232
5. Pappan, K. L., Pan, Z., Kwon, G., Marshall, C. A., Coleman, T., Goldberg, I. J., McDaniel, M. L., Semenkovich, C. F. (2005) Pancreatic ß-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion. J. Biol. Chem. 280: 9023-9029
6. Kwon, G., Marshall, C. A., Liu, H., Pappan, K. L., Remedi, M. S., McDaniel, M. L. (2006) Glucose-stimulated DNA synthesis through mTOR is regulated by KATP channels: Effects on cell cycle progression in rodent islets. J. Biol. Chem. 281: 3261-3267
7. Kwon, G., Cruz, W. S., Marshall, C. A., Pappan, K. L., Imachi, H., Souza, S. C., Zhang, C. -Y., McDaniel, M. L., Greenberg, A. S. (2006) Regulation of adipocyte differentiation-related protein expression by isolated rat islets via mTOR activation. In preparation.