mTOR Regulation of VSMC Differentiation

mTOR 对 VSMC 分化的调节

• 批准号: 6770641
• 负责人: Eva Maria Rzucidlo
• 金额: $ 10.78万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770641
• 关键词: Adenoviridae; SDS polyacrylamide gel electrophoresis; autoradiography; biological signal transduction; capillary bed; cell differentiation; cell line; cell morphology; extracellular matrix; gene expression; gene mutation; genetic regulation; genetic translation; polymerase chain reaction; ribosomal proteins; serine threonine protein kinase; sirolimus; transfection /expression vector; vascular smooth muscle; western blottings

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for my development of an academic career in vascular surgery. Through an integrated program between the Department of Vascular Surgery and the Department of Pharmacology and Toxicology, a command of intracellular signaling mechanisms, as applied to vascular disease, will be secured. Dr. Richard J. Powell, M.D., will mentor the principal investigator's scientific development. Dr. Powell is an NIH-funded researcher in vascular biology with extensive experience with a bi-layer co-culture model used to better define the effects of endothelial cells (ECs) on vascular smooth muscle cells (VSMCs) function and behavior. Dr. Powell has trained numerous residents and fellows who have gone on to successful academic careers. To enhance the training, this program will enlist the expertise of Dr. Kathleen A. Martin, Assistant Professor of Surgery and of Pharmacology and Toxicology. She is an expert in intracellular signaling mechanisms, specifically the mTOR pathway. In addition, an advisory committee of highly regarded scientists will provide scientific and career advice. My research will focus on the intracellular signaling mechanisms involved in phenotypic modulation, migration and proliferation of VSMCs. Rapamycin inhibits VSMC proliferation, protein synthesis and migration in vitro. We have recently demonstrated that rapamycin stimulates VSMC differentiation. VSMC differentiation was determined by contractile morphology and upregulation of contractile proteins. Rapamycin inhibits mTOR, a signaling protein known to regulate translation initiation pathways. The downstream effectors of the mTOR pathway, which modulate these pleomorphic effects, have not been determined. The specific aims include: 1) to determine whether rapamycin sensitive mTOR downstream effectors S6K1 or S6K2 oppose VSMC differentiation; 2) to determine whether rapamycin sensitive mTOR downstream effector 4E-BP1/elF-4E oppose VSMC differentiation; and 3) to determine if rapamycin effects are similar in VSMC from different vascular beds. The long-term objective is to determine the signaling pathways which mediate the VSMC intimal hyperplastic response, with the aim of identifying novel, cell-type specific targets for therapeutic intervention.

描述（由申请人提供）： 该建议描述了我为我在血管外科手术领域发展职业的5年培训计划。 通过血管外科系与药理学和毒理学系之间的综合计划，将确保一种细胞内信号传导机制的指挥，以适用于血管疾病。 医学博士理查德·J·鲍威尔（Richard J. Powell）博士将指导主要研究者的科学发展。 Powell博士是NIH资助的血管生物学研究人员，具有丰富的经验，具有双层共培养模型，用于更好地定义内皮细胞（ECS）对血管平滑肌细胞（VSMC）功能和行为的影响。 鲍威尔博士已经培训了许多从事成功学术职业的居民和研究员。 为了增强培训，该计划将获得手术助理教授，药理学和毒理学助理教授Kathleen A. Martin博士的专业知识。 她是细胞内信号传导机制的专家，特别是MTOR途径。 此外，由备受推崇的科学家组成的咨询委员会将提供科学和职业建议。 我的研究将集中于参与表型调节，迁移和VSMC增殖的细胞内信号传导机制。雷帕霉素在体外抑制VSMC增殖，蛋白质合成和迁移。 我们最近证明雷帕霉素会刺激VSMC分化。 VSMC分化是通过收缩形态和收缩蛋白上调确定的。 雷帕霉素抑制MTOR，这是一种已知调节翻译起始途径的信号蛋白。 尚未确定调节这些多态效应的mTOR途径的下游效应子。 具体目的包括：1）确定雷帕霉素敏感的MTOR下游效应子S6K1或S6K2是否反对VSMC分化； 2）确定雷帕霉素敏感的MTOR下游效应子是否反对VSMC分化； 3）确定不同血管床的VSMC中雷帕霉素效应是否相似。 长期目标是确定介导VSMC内膜增生反应的信号传导途径，目的是识别用于治疗干预的新型细胞类型的特定靶标。