GENETICS OF GROWTH: ROLES OF IGFS AND GROWTH HORMONE

一项基因研究计划被提议用于调查，与 细胞、分子和生化分析，促进生长的作用 胰岛素样生长因子(IGF)和生长激素(GH)的研究 已在实验室获得的突变小鼠模型或 将通过基因打靶产生。最近的证据表明 胰岛素样生长因子配体和受体系统的中枢参与 胚胎和出生后的生长提供了一个强有力的迹象 旨在解决遗传成分关键问题的拟议项目 与胎儿宫内发育有关的生长过程 人类的发育迟缓和各种矮小和过度生长综合症。 在本方案的背景下：(A)将努力澄清 先前已鉴定的未知受体(XR)的分子性质 从基因上看，这显然介导了一些促进生长的 IGF-II的功能；(B)XR可能是胰岛素受体的假设 (IR)在I型IGF受体缺失的情况下采取机会主义行动 (IGF1R)将使用同时缺乏IR和IGR1R的双重突变体进行测试；(C) IGF-I和IGF-II在胚胎生长中的相对作用将是 详细检查；(D)缺乏2型的小鼠的过度生长表型 IGF受体或携带包含Igf2连锁H19基因的缺失 将被分析；(E)胎盘和胚胎之间的关系 将通过胚胎操作来评估生长；(F)关系 生长激素和胰岛素样生长因子-I在促进出生后生长中的作用将被调查 比较强调长骨发育，有针对性地 GH受体基因的破坏和有条件地消融Igf1 基因在肝脏或骨骼中，以研究循环和骨的相对作用 本地产生的IGF-I；和(G)胰岛素受体的作用 胰岛素样生长因子生长信号通路中的底物-1(IR-1)(S)将是 从基因上进行调查，而编码cDNA的鉴定 将通过细胞培养寻找相同途径的效应器 使用缺乏IGF1R和/或IR受体的细胞系的实验。 我们提出的遗传计划应该允许建立 已定义突变与其表型之间的因果关系 后果，并具有以下优势，即问题将在 在整个发育中的模式生物体的背景下。

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.