ROLE OF ENDOCRINE SECRETIONS IN GROWTH AND DEVELOPMENT

IGF-I发挥广泛的内分泌、旁分泌或自分泌作用， 作用于多种细胞和组织。 大鼠和其他哺乳动物 种，一个复杂的家族IGF-I mRNA来源于一个单一的基因。 我们的中心假设是IGF-I mRNAs的异质性和 编码的前体是IGF-I发挥其 行动的多样性。 不同IGF-I mRNA编码的不同IGF-I前体可 确定IGF-I对细胞内或细胞外位点的靶向， 作用或可能影响IGF-I与受体的相互作用或结合 proteins. 拟议的研究将通过以下方式检验这些可能性： 定义IGF-I的结构，所述IGF-I的结构由以下的翻译产生： （ii）分析细胞内定位、加工和 培养细胞系统中IGF-I前体的分泌（iii）使用模型 细胞系统和转基因小鼠，以评估 IGF-I前体。 转基因小鼠代表了研究 扰动的发展和长期后果 特异性IGF-I前体的合成。 我们的目标是生长激素 (GH)特异性IGF-I pecursors独立表达到肝脏， 循环IGF-I的主要来源，并分析这种靶向是否可以 纠正GH和IGF-I缺陷小鼠的生长迟缓。 这将 解决IGF-I生理学中的两个中心问题：IGF-I在 刺激生长独立于生长激素和循环的贡献 与局部合成的IGF-I相比， 在发展中成长。 调节细胞凋亡的转录和转录后机制 不同IGF-I mRNA的表达可以决定IGF-I的表达位点、水平和分布。 和IGF-I表达的时间过程，从而确定IGF-I表达的位点和时间 IGF-I的作用。 我们将分析这些机制（i） 表征调节IGF-I的GH依赖性启动子 （二）在转录水平上进行综合评估 IGF-I在mRNA水平的转录后调控 稳定 我们已经证明大分子形式的IGF-I 具有长3 '非翻译区（3' UTs）的mRNA比具有长3 '非翻译区（3' UTs）的mRNA稳定性差。 较小的形式。 因此，我们将定义介导 这些mRNA的不稳定性，确定糖皮质激素是否 使这些mRNA不稳定，以及这是否会导致IGF-I减少， 合成.

IGF-I exerts a wide spectrum of endocrine, paracrine or autocrine actions on multiple cells and tissues. In rat and other mammalian species, a complex family of IGF-I mRNAs derived from a single gene. Our central hypothesis is that the heterogeneity of IGF-I mRNAs and encoded precursors is integral to tbe ability of IGF-I to exert its diversity of actions. Different IGF-I precursors encoded by different IGF-I mRNAs could determine targeting of IGF-I to intracellular or extracellular sites of action or could influence IGF-I interactions with receptors or binding proteins. Proposed studies will test these possibilities by (i) defining the structures of the IGF-I that result from translation of different mRNAs (ii) analysing intracellular localiation, processing and secretion of IGF-I precursors in cultured cell systems (iii) using model cell systems and transgenic mice to assess the biological actions of IGF-I precursors. Transgenic mice represent unique models to study the developmental and long term consequences of perturbations in the synthesis of specific IGF-I precursors. We aim to target growth hormone (GH) independent expression of specific IGF-I pecursors to liver, the major source of circulating IGF-I and analyse whether such targeting can correct growth retardation in GH and IGF-I deficient mice. This will address two central questions in IGF-I physiology: the role of IGF-I in stimulating growth independent of GH and the contribution of circulating versus locally synthesized IGF-I in stimulating somatic and tissue growth during development. Transcriptional and post-transcriptional mechanisms that regulate the expression of different IGF-I mRNAs could determine the sites, levels and time course of IGF-I expression and thereby the locus and time course of IGF-I action. We will analysc these mechanisms by (i) characterizing the GH dependent promotor (s) that regulate IGF-I synthesis at the level of transcription (ii) assessing post-transcriptional control of IGF-I synthesis at the level of mRNA stability. We have demonstrated that large molecular forms of IGF-I mRNA with long 3'untranslated regions (3'UTs) are less stable than smaller forms. We will therefore define the sequences that mediate instability of these mRNAs, establish whether glucocorticoids destabilize these mRNAs and whether this results in reduced IGF-I synthesis.