IGFS AND SKELETAL MUSCLE CELL DIFFERENTIATION

根据医师科学家奖(PSA)，候选人、 赞助商和第一阶段咨询委员会与 儿科，已经构建了详细的2期5年 旨在为应聘者提供强化培训的培训计划 培训和研究经验。第一阶段由11名毕业生组成 5个部门的部门课程，定期参加各种研讨会， 和三次实验室旋转。这一体验是仿照 宾夕法尼亚大学生物医学博士研究生项目 加州，旧金山，将满足第一阶段的要求 PSA。Il阶段是在直接监督下进行的95%的实验室研究 赞助商的名字。 在第二阶段，候选人的研究工作将集中在 胰岛素样生长因子(IGF)调节肌肉的机制 细胞分化。这一目标将由L)学习来实现 胰岛素样生长因子作用的潜在靶基因 分化过程，2)检测哪些IGF受体亚型介导 胰岛素样生长因子的生肌作用；3)探讨胰岛素样生长因子的作用 结合蛋白(BP)在调节IGF诱导分化中的作用。在.期间 这一提议，将检验以下三个假设：L)认为政府间气候变化框架 影响骨骼肌细胞生长或分化的决定 通过调节视网膜母细胞瘤蛋白(PRB)的磷酸化， 细胞周期机械的调节器，当磷酸化时促进 生长，但当低或非磷酸化时促进分化；2) 独立于IGF-I受体的IGF-II受体可以发出信号 3)IGFBPs可增强或抑制IGF的作用， 调节胰岛素样生长因子诱导的肌肉细胞分化。为了测试这些 假设我们提出的具体目的如下：L)考察效应 胰岛素样生长因子对pRb磷酸化的影响及对主要蛋白表达的影响 细胞周期蛋白依赖性激酶(CDK)及其调控亚单位细胞周期蛋白 以及调节pRb磷酸化的CDK抑制剂；2) 显性阴性的IGF-I受体功能失活 突变以确定IGF-II受体是否能向肌肉细胞发出信号 独立于IGF-I受体的分化；以及3)检查 肌细胞IGFBPs调节胰岛素样生长因子诱导分化的能力 用反义CRNAs抑制其表达。 这些研究应该通过以下方式提供对机制的进一步了解 其中IGF调节肌肉细胞分化。研究这些链接 生长因子信号和细胞周期调节之间可能有 对理解正常过程和 异常增殖和分化。成功完成这项工作 该计划将使候选人具备追求独立职业生涯的能力 研究内分泌功能的分子基础。

In accordance with the Physician Scientist Award (PSA), the candidate, the sponsor, and the Phase I advisory committee, in conjunction with the Department of Pediatrics, have constructed a detailed 2-phase 5-year training program intended to provide the candidate with an intensive training and research experience. Phase I consists of eleven graduate division courses in 5 departments, regular attendance at various seminars, and three laboratory rotations. This experience, modeled after the graduate Ph.D. program in Biomedical Sciences at the University of California, San Francisco, will fulfill the Phase I requirements of the PSA. Phase Il is 95-lOO% laboratory research under the direct supervision of the sponsor. During phase II, the candidate's research effort will focus on the mechanisms by which the insulin-like growth-factors (IGFs) regulate muscle cell differentiation. This objective will be approached by l) studying potential target genes of IGF action which play a role in the differentiation process, 2) examining which IGF receptor subtypes mediate the myogenic effect of IGFs, and 3) exploring the potential role of IGF binding proteins (BPs) in modulating IGF-induced differentiation. During this proposal, the following three hypotheses will be tested: l) that IGFs influence the decision of skeletal muscle cells to grow or differentiate by regulating the phosphorylation of retinoblastoma protein (pRB), a key regulator of the cell cycle machinery, which when phosphorylated promotes growth but when hypo- or unphosphorylated promotes differentiation; 2) that IGF-II receptor, independently of IGF-I receptor, can signal myogenesis; and 3) that IGFBPs, which may enhance or inhibit IGF action, modulate IGF-induced differentiation in muscle cells. To test these hypotheses we propose the following specific aims: l) Examine the effects of IGFs on pRB phosphorylation and on the expression of the principal cyclin-dependent kinases (CDKs) and their regulatory subunits, the cyclins and the CDK inhibitors, which regulate pRB phosphorylation; 2) Functionally inactivate the IGF-I receptor with a dominant negative mutation to determine if the IGF-II receptor can signal muscle cell differentiation independently of the IGF-I receptor; and 3) Examine the ability of muscle cell IGFBPs to modulate IGF-induced differentiation by inhibiting their expression with antisense cRNAs. These studies should provide further understanding of the mechanisms by which IGFs regulate muscle cell differentiation. Studying the links between growth factor signaling and cell cycle regulation could have general implications for understanding the processes of normal as well as aberrant proliferation and differentiation. Successful completion of this program will equip the candidate to pursue an independent career investigating the molecular basis of endocrine function.