Day 1 :
NIDDK, NIH, USA
Time : 09:05-09:30
Simons received his Ph.D from Harvard University. After a postdoctoral fellowship at Univ. of California, SF, he moved to the NIH and became Chief of the Steroid Hormones Section in 1985. He has published over 150 papers, and has 5 patents, in the field of the mechanism of steroid hormone action, with an emphasis on the role of transcription co factors. He has served on review boards of numerous grant review panels and journals.
A common but unexplained observation regarding steroid receptor-regulated gene induction is that the maximal activity (Amax) and steroid concentration required for half-maximal activity (EC50) are not fixed parameters for a specific steroid. Instead, changing concentrations of factors can modulate the values of Amax and EC50, even for a selected gene in a given cell line. Such phenomena are essential for differential control of gene expression during development, differentiation, and homeostasis. We have developed, in collaboration with Dr. Carson Chow (NIH), an experimentally supported mathematical model of steroid hormone action that not only accounts for these changes in Amax and EC50 but also utilizes the changes to obtain previously unobtainable information about the mechanism of action of the modulatory factors. The basis of this model is that the dose-response curve for product formation follows Michaelis-Menten kinetics to give a first-order Hill plot. A competition assay has been developed from this model that determines both the relative positioning in the overall reaction sequence, and the kinetically determined mechanism of action, of any two competing factors. As examples of the utility of this competition assay, an analysis of new modulatory factors affecting both glucocorticoid receptor-mediated gene induction and repression will be presented. This information not only establishes an internally consistent framework for categorizing factor actions but also permits a clinically relevant, more targeted approach to modifying the expression of steroid-regulated target genes that should be accompanied by fewer side effects.
University of Florida, USA
Time : 10:00-10:25
Mandal is a native of India and a naturalized citizen of the United State of America. He is board certified in Internal\r\nMedicine and Nephrology (not yet recertified in nephrology). Diabetes Mellitus is the most common cause of kidney failure\r\nin the USA and worldwide. This strong association between diabetes and kidney failure has inspired Dr. Mandal to develop\r\nthe framework of Mandal Diabetes Research Foundation to assist diabetic patients in living a good life with medical\r\ntreatment, and avoiding dialysis. He is a published author/editor of 12 books and more than 100 articles on research in\r\ndiabetes and kidney disease. He is a two-time Fulbright Scholar and a visiting professor of 23 countries which permitted\r\nlectures on diabetes, high blood pressure and kidney diseases on five continents of the world. His astute knowledge and total\r\ndedication help patients get better and to live a good life. His convictions are that in the office patients come first, at home\r\nchildren come first. Roses are his love, hence rose gardening is his hobby.
Fasting blood glucose (FBG) > 126 mg/dL (7mmol/L) and /or glycosylated hemoglobin (HbA1c) > 6.5% have traditionally\r\nbeen used as a marker for the diagnosis of diabetes and initiation of a treatment plan. Despite the use of these diagnostic\r\nmarkers and a plethora of oral hypoglycemic agents, diabetic complications namely, cardiovascular disorders, renal failure\r\nand dialysis, and amputations, are on the rise. Therefore a reasonable concern is that either the definition of diabetes or the\r\nprevalent therapy with oral hypoglycemic agents, or both, are faulty. Abundant literature is available regarding the\r\nimportance of using 2-hour postprandial glucose (2hPPG) in glycemic control for the prevention of diabetic complications.\r\nA robust association has been shown between 1-h or 2-h postprandial hyperglycemia (> 200 mg/dL; 11.1mmol/L) and\r\ncardiovascular disorders and mortality. Notwithstanding the availability of such important information, 2hPPG control is still\r\nunder used in clinical practice of diabetes care. Worse than that, popularity of use of FBG and /or HbA1c as a guide for\r\ndiabetes care has permitted an incorrect diagnosis of Type 2 diabetes in numerous hypertensive patients treated with a\r\nthiazide diuretic and having elevated glucose levels followed by mistreatment with oral hypoglycemic agents. The result is\r\nsubsequent development of overt diabetes in many individuals, some of them are riddled with numerous complications such\r\nas foot ulcer, gangrene, kidney failure or heart disease. This article is dedicated to redirecting the attention from using FBG\r\nand or HbA1c to 2hPPG as a fundamental tool for evaluation of diabetes and to focus on therapy encompassing 2hPPG.\r\nEvidence has emerged from basic as well as clinical research claiming the importance of control of postprandial\r\nhyperglycemia in the prevention of diabetic complications. Prevention of diabetic complications is attainable by control of\r\npostprandial hyperglycemia with the prescription of a combination of Glargine insulin twice daily (12 hours apart) and\r\ntreatment of glycemic excursions with fast-acting insulin.
University of California-Riverside, USA
Keynote: Vitamin D receptor (VDR) regulation of voltage-gated chloride channels by ligands preferring the VDR-alternative pocket (VDR-AP)
Time : 10:20-10:45
Anthony W. Norman is a distinguished professor emeritus of biochemistry and biomedical sciences at the University of California, Riverside and one of the world\\\\\\\'s foremost experts on vitamin D. Through May, 2011, Norman had been credited with over 800 scientific publications dating back to 1959
Based on molecular modeling and ligand binding studies it has been postulated that the vitamin D receptor (VDR) contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that mediate rapid responses and regulation of gene transcription, respectively. The data obtained from molecular mechanics docking studies predict that the major blood metabolite, 25(OH)-vitamin D3 (25D3), selectively bind to the VDR-AP while the steroid hormone 1α,25(OH)2-vitamin D3 (1,25D3 ) binds equally well to both pockets, however analog JN prefers the alternative pocket and analog HL is an inhibitor of genomic responses. 1,25D3, 25D3, and JN each rapidly stimulated voltage-gated outwardly rectifying chloride channels (ORCC) in TM4 sertoli cells. In a dose response study, 25D3 and 1,25D3 were equipotent in stimulating ORCC rapid response while 1 nM 1,25D3 was 1000x more potent than 25D3 in stimulating gene expression. These results are consistent with the concept that whereas ligand occupancy of the VDR-GP initiates genomic actions, occupancy of the VDR-AP is essential to initiate signaling required for rapid opening of ORCC. The VDR-AP agonist effects of 1,25D3, 25D3 and JN are absent following pretreatment of TM4 cells with VDR siRNA. In COS-1 cells transfected with VDRwt or a mutant construct lacking the DNA binding domain, 1,25D3 and 25D3 potentiate the opening of ORCC. Cells transfected with VDR mutants lacking either the ligand binding domain or the hinge/loop region lost this response to the ligands. The fact that 25D3 is equipotent to 1,25D3 in mediating rapid responses possibly suggests a paradigm shift in thinking about the ability of 25D3 in vivo to generate biological responses.