IGFS AND SKELETAL MUSCLE CELL DIFFERENTIATION

根据医生科学家奖（PSA），候选人， 赞助商，第一阶段咨询委员会，连同 儿科，已建成详细的2期5年 培训计划旨在为候选人提供一个密集的 培训和研究经验。第一阶段由11名毕业生组成 在5个部门开设司级课程，定期参加各种研讨会， 三个实验室轮换。 这种经验，仿照 研究生博士在生物医学科学的计划在大学的 加州、旧金山弗朗西斯科将满足 PSA。第二阶段是95- 100%的实验室研究， 的赞助商。 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（IGFs）调节肌肉的机制 细胞分化这一目标将通过l）研究 IGF作用的潜在靶基因，这些基因在 分化过程，2）检查哪些IGF受体亚型介导 IGF的生肌作用; 3）探讨IGF的潜在作用 结合蛋白（BP）在调节IGF诱导的分化中的作用。期间 根据这一建议，将检验以下三个假设：l）IGFs 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， 细胞周期机制的调节剂，当磷酸化时促进 生长，但当低磷酸化或未磷酸化时促进分化; 2） IGF-II受体，独立于IGF-I受体， 肌生成;和3）IGFBPs，其可以增强或抑制IGF作用， 调节IGF诱导的肌细胞分化。测试这些 假设我们提出以下具体目标：l）检查效果 IGFs对pRB磷酸化的影响以及对主要的 细胞周期蛋白依赖性激酶（CDKs）及其调节亚基，细胞周期蛋白 以及调节pRB磷酸化的CDK抑制剂; 2） IGF-I受体功能性失活 突变，以确定IGF-II受体是否可以信号肌细胞 独立于IGF-I受体的分化;和3）检查 肌细胞IGFBPs调节IGF诱导分化的能力 用反义cRNA抑制它们的表达。 这些研究应该通过以下方式提供对机制的进一步理解： 哪些IGFs调节肌肉细胞分化。研究链接 生长因子信号和细胞周期调节之间的联系 对于理解正常过程以及 异常增殖和分化。成功完成本 该计划将使候选人能够追求独立的职业生涯 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.