GENETICS OF GROWTH: ROLES OF IGFS AND GROWTH HORMONE

点击翻译按钮获取中文摘要

A genetic research program is proposed to investigate, in conjunction with cellular, molecular and biochemical analyses, the growth-promoting roles of insulin-like growth factors (IGFs) and growth hormone (GH), by using mutant mouse models that are either already available in the laboratory or will be generated by gene targeting. Recent evidence demonstrating the central involvement of the IGF system of ligands and receptors in embryonic and postnatal growth has provided a strong indication for the proposed project designed to address key questions on genetic components of the growth process that are related with cases of intrauterine growth retardation and a variety of dwarfing and overgrowth syndromes in humans. In the context of this program: (a) attempts will be made to elucidate the molecular nature of an unknown receptor (XR) previously identified genetically, which apparently mediates some of the growth-promoting functions IGF-II; (b) the hypothesis that XR may be the insulin receptor (IR) acting opportunistically in the absence of the type-1 IGF receptor (IGF1R) will be tested using double mutants lacking both IR and IGR1R; (c) the relative roles of IGF-I and IGF-II in embryonic growth will be examined in detail; (d) overgrowth phenotypes in mice lacking the type-2 IGF receptor or carrying a deletion that includes the Igf2-linked H19 gene will be analyzed; (e) the relationship between placental and embryonic growth will be assessed by embryo manipulations; (f) the relationship between GH and IGF-I in promoting postnatal growth will be investigated comparatively with emphasis on long-bone development, by targeted disruption of the GH receptor gene and by conditional ablation of the Igf1 gene in liver or in bones, to study the relative roles of circulating and locally-produced IGF-I; and (g) the role of the insulin receptor substrate-1 (IRS-1) in the IGF growth-signaling pathway(s) will be investigated genetically, while the identification of cDNAs encoding effectors of the same pathway will be sought through cell culture experiments utilizing cell lines lacking IGF1R, IR or both receptors. The genetic program that we propose should allow the establishment of causal relationships between defined mutations and their phenotypic consequences, and has the advantage that questions will be addressed in vivo in the context of the entire developing model organism.