Autoimmune and non-immune apoptosis, or programmed death, of pancreatic beta cells results in type 1 diabetes mellitus. Normal beta-cell survival entails complex regulation of multiple hormones and fundamental growth factors, including the insulin-like growth factors (IGFs). IGF binding proteins (IGFBPs) sequester IGFs in body tissues and blood, thereby controlling bioavailability of lGFs for their receptors. IGFBPs dramatically impact cell proliferation, apoptosis, and physiology via both IGF-dependent and IGF-independent mechanisms. Work in several cell culture and animal models has confirmed that the pancreatic islets provide a fertile environment for actions of multiple IGF axis components. Manipulating this axis to understand and ultimately control the pathways regulating beta cell survival is key to multiple strategies for restoring insulin secretion. Recently, it has been discovered that IGFBP-3, the major IGFBP in serum, induces apoptosis in diverse cancer cell types via direct, functional interactions with the nuclear retinoic X receptor-alpha (RXR-alpha), the first nuclear receptor identified for any IGFBP. Several cytokines have been implicated in beta cell apoptosis, including tumor necrosis factor-alpha (TNF-alpha). We have recently discovered that TNF-alpha-induced beta cell apoptosis requires de novo transcription of IGFBP-3. Moreover, we have discovered that TNF-alpha induces IGFBP-3 production and increases the nuclear content of IGFBP-3 in beta cells. We have developed two new mouse models; a transgenic designed to specifically over-express IGFBP-3 in the islets, and mice which lack IGFBP-3, but possesses alleles associated with type 1 diabetes (namely the iddm alleles of the non-obese diabetic mouse. These latter NOD/BP3-/-mice appear to manifest improved glucose tolerance in vivo, suggesting that loss of IGFBP-3 may protect from beta-cell apoptosis. These data are compelling to pursue because they present novel targets for controlling beta cell survival and for improving beta cell function. Our central hypothesis is that IGF axis components, IGFBP-3 and IGF-I in particular are critical regulators of beta-cell survival and insulin secretion and therefore play central roles in the pathogenesis of type 1 and type 2 diabetes. We propose to: 1) determine the relationship between IGFBP-3 and RXR-alpha in beta-cell apoptosis and dysfunction; 2) develop novel transgenic rodent models overexpressing select native and mutant IGF axis components in an islet-specific manner; 3) determine the requirement of IGFBP-3 for beta-cell apoptosis in vivo, and 4) assess whether overexpression of IGFBP-3 antagonists in the islets protects NOD mice from developing diabetes. These studies promise to improve our understanding of the pathogenesis of diabetes and may open novel therapeutic approaches to prevention and treatment of diabetes. The UCLA Department of Pediatrics has dedicated extensive resources to support the research activities and career development of its junior faculty. This Department has established mentoring programs to transition junior faculty from dependence to independence, and, ultimately, interdependence as pediatrician scientists. The resources of the candidate's department will leverage the support from this grant on a """"""""dollar-for-dollar"""""""" basis, and thereby propel not only the proposed scientific work but also the emergence of the candidate as an independent pediatrician-scientist during the time period of this award.
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