| Laboratories Paul J. Beisswenger, MD William B. Kinlaw, III, MD Lee A. Witters, MD Paul J. Beisswenger, MD My research program is focused on determining the role of enzymatic control of non-enzymatic glycation in the cellular and tissue damage associated with diabetes. My focus is on factors that regulate toxic oxidative and dicarbonyl compounds, and their resultant Advanced oxidative and Glycation Endproducts (AGEs), both of which are produced in excess in diabetes and play an important role in the development of diabetic complications. My laboratory is also at the very forefront of research in the new area of enzymatic deglycation in mammalian systems. My most recent research funding has been provided to study biomarkers that can potentially predict susceptibility to diabetic vascular complications. We have recently obtained a triple quad LC/MS-MS that can quantify a number of AGEs and oxidative products. With these tools we are in a unique position to combine studies of human populations with powerful analytic laboratory techniques and new paradigms to address some of the important outstanding questions regarding diabetic complications. Physician profile: Paul J. Beisswenger, MD William B. Kinlaw, III, MD Our laboratory is focused on elucidating the role of a gene called "S14" in breast cancer biology. The S14 gene is amplified in some breast cancers, and over-expressed in most cases. Breast cancers require an ongoing source of fatty acids, and die if deprived of them. S14 acts, in the cell nucleus, to transmit signals regarding the hormonal milieu and nutrient availability, which ultimately govern the expression of genes required for lipid synthesis. We find that a high level of S14 in breast tumors potends an aggressive course, and that depriving the cells of S14 causes them to die by apoptosis. Our current efforts are aimed at validating S14 as a therapuetic target in breast cancer. Physician profile: William B. Kinlaw, III, MD Lee A. Witters, MD Our laboratory's interest is directed to understanding how cells and tissues respond to a number of stresses, such as the availability of oxygen and metabolic substrates like glucose, and how the rates of fat and cholesterol synthesis and degradation are regulated. A major area of interest relates to the molecular characterization of a novel protein, kinase, that is activated by 5'-AMP. This enzyme, designated AMP-activated protein kinase (AMPK), is activated under conditions of low blood flow (ischemia), low oxygen concentrations (hypoxia), or when glucose is limiting for cellular metabolism. It has a wide tissue distribution and is a unique member of a much larger protein kinase family with homologs in yeast, plants, C. elegans and several mammalian species. The enzyme consists of three subunits: a, b and g. The first is its catalytic subunit and the latter two are non-catalytic regulatory subunits. The metabolite-sensing function of AMPK homologs has been preserved through evolution, indicating the critical nature of its cellular function. Using several model systems including transgenic mice, C. elegans, and cultured cell lines, current experiments are addressing the functions of all three kinase subunits; "upstream" activating AMPK kinases (LKB1, CaMKK); the nature of the intracellular substrates for the kinase and their physiologic impact; and the regulation of kinase activity by hormones and other extracellular signals. These systems have defined the importance of AMPK and its regulation in a number of pathophysiologic circumstances (e.g. cancer cell survival, diabetes mellitus, obesity/eating behaviors) and normal organ physiology (e.g. muscular exercise). | | Make an Appointment DHMC Related Links |
