REGULATION OF FETAL HEPATIC DEVELOPMENT BY INSULIN

胰岛素对胎儿肝脏发育的调节

• 批准号: 3735230
• 负责人: PHILIP GRUPPUSO
• 金额: --
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3735230
• 关键词: DNA replication; affinity labeling; binding proteins; biological signal transduction; embryo /fetus tissue /cell culture; embryology; gestational age; gestational diabetes mellitus; growth factor receptors; hepatocyte growth factor; insulin; laboratory rat; liver cells; phosphorylation; prenatal growth disorder; protein biosynthesis; transforming growth factors

The objective of this project is to investigate mechanisms by which insulin regulates the growth of rat fetal hepatocytes in primary culture. The overall hypothesis is that insulin action is mediated, at least in part, through effects on the actions of other polypeptide growth factors. Since insulin and growth factor signal transmission both involve reversible phosphorylation of proteins, we will focus on protein phosphorylation and protein phosphatase regulation. The hypotheses to be tested are based in large part on preliminary data which have demonstrated the following: [1] Fetal rat hepatocytes in primary culture grow independently of serum or added mitogens; [2] This factor-beta (TGF-beta); [3] Insulin at physiologic concentrations potentiates serum-independent growth by approximately 50%; [4] This insulin-potentiation is abolished in hepatocytes from growth retarded fetuses. The specific aims of this project include the following: [1] Determine the ontogeny of serum-independent growth of fetal and neonatal rat hepatocytes and the autocrine/paracrine factors responsible for this growth; [2] Investigate mechanisms mediated through effects on insulin-like growth factor (IGF) receptors and binding proteins by which insulin potentiates fetal hepatocyte growth; [3] Investigate mechanisms mediated by protein phosphorylation by which insulin potentiates fetal hepatocyte growth; [4] Study corresponding mechanisms by which glucagon and TGF-beta inhibit fetal hepatocyte growth; [5] Compare the growth regulatory effects and mechanisms of action of insulin, glucagon and TGF-beta in fetal hepatocytes from normal, growth retarded and macrosomic fetuses. We anticipate that these studies will provide insight into the mechanisms by which fetal hepatic growth is augmented in fetuses of diabetic mothers.

该项目的目的是研究胰岛素的机​​制 调节大鼠胎儿肝细胞在原发性培养中的生长。 这 总体假设是，胰岛素作用至少部分介导 通过对其他多肽生长因子的作用的影响。 自从 胰岛素和生长因子信号传播都涉及可逆 蛋白质的磷酸化，我们将专注于蛋白质磷酸化和 蛋白质磷酸酶调节。 要测试的假设基于 初步数据的很大一部分已证明以下内容：[1] 原发性培养的胎儿大鼠肝细胞独立于血清或 添加了有丝分裂剂； [2]这个因子β（tgf-beta）; [3]生理学的胰岛素 浓度使血清独立的生长增长了约50％； [4]这种胰岛素抑制在生长的肝细胞中被取消 胎儿迟钝。 该项目的具体目的包括以下内容：[1]确定 胎儿和新生大鼠肝细胞的血清非依赖性生长的个体发育 以及负责这种增长的自分泌/旁分泌因素； [2] 研究通过对胰岛素样生长的影响介导的机制 因子（IGF）受体和结合蛋白，胰岛素增强 胎儿肝细胞的生长； [3]研究蛋白质介导的机制 胰岛素增强胎儿肝细胞生长的磷酸化； [4] 研究相应的机制，胰高血糖素和TGF-β抑制胎儿 肝细胞生长； [5]比较生长调节效应和机制 从胎儿肝细胞中胰岛素，胰高血糖素和TGF-β的作用 正常，生长迟缓和大型胎儿。 我们预计这些 研究将洞悉胎儿肝的机制 糖尿病母亲的胎儿增加了生长。