Function of Notch Signaling in Vascular Smooth Muscle

Notch信号在血管平滑肌中的功能

• 批准号: 7340695
• 负责人: AARON PROWELLER
• 金额: $ 13.33万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340695
• 关键词: Adhesions; Adult; Advisory Committees; Animals; Apoptosis; Arterial Disorder; Attention; Biology; Blood Vessels; CADASIL; Cancer Center; Cardiology; Cardiovascular system; Cell Differentiation process; Cell physiology; Cells; Cerebrum; Collaborations; Complex; Core Facility; Critical Pathways; Data; Development; Disease; Dose; Embryo; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Hematopoietic; Homeostasis; Human; Indium; Injury; Introns; Laboratories; Lead; Ligands; Maintenance; Mentors; Molecular; Mus; Muscle function; Mutation; Myosin Heavy Chains; Numbers; Organ; Pattern; Pear; Pennsylvania; Phenotype; Physicians; Play; Principal Investigator; Process; Reagent; Regulation; Research; Resources; Role; Scientist; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Smooth Muscle Myosins; Supervision; Syndrome; System; Technology; Tissues; Training; Training Programs; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; Universities; Vascular Endothelium; Vascular Smooth Muscle; abstracting; angiogenesis; base; career; design; migration; mouse Smc1l1 protein; mouse Smc1l2 protein; myocardin; notch protein; programs; promoter; receptor; response; success

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program designed to develop an academic career for the candidate in vascular biology. The research focuses on vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation with emphasis on the role of cell signaling in these processes. The activities proposed rely on a collaborative program of study under co-supervision of two internationally recognized principal investigators, Drs. Michael S. Parmacek, an expert in transcriptional regulation of VSMCs, and Warren S. Pear, a leader in the field of Notch signaling. Together, the candidate will utilize both intellectual and proprietary resources from these laboratories with further guidance by an advisory committee of distinguished physicians and scientists. Participation in didactic courses and research seminars will enhance the educational success of the program. The research plan centers on a role for Notch signaling in the differentiation and function of VSMCs. These cells have the unique capacity to alter their phenotype from contractile to proliferative activity in response to vascular injury and in the setting of vasculoproliferative disorders. Notch signaling is a well-described modulator of cell differentiation, proliferation and apoptosis, and animals deficient in select Notch signaling components display disrupted vascular development and homeostasis. Preliminary studies reveal that Notch signaling modulates VSMC-specific gene expression leading to the hypothesis that Notch signaling has an important role in the phenotypic regulation of VSMCs. Accordingly, specific aims of this proposal are to (1) determine the molecular basis of Notch signaling-induced smooth muscle gene expression; (2) determine the impact of dysregulated Notch signaling in established SMC differentiation systems and in mature VSMCs; and (3) determine the effect of inhibiting SMC-specific, RBP-Jk-dependent Notch signaling in mice. The Molecular Cardiology Research Center and the Abramson Cancer Center of the University of Pennsylvania provide extensive resources, collaborations, core facilities and intellectual expertise. As such, this is an ideal setting for the candidate to acquire mentored training towards an independent career as a physician-scientist. (End of Abstract)

描述（由申请人提供）： 该建议描述了一项为期5年的培训计划，旨在为血管生物学候选人发展学术生涯。 该研究的重点是血管平滑肌细胞（VSMC）分化和表型调节，重点是细胞信号在这些过程中的作用。 拟议的活动依赖于两名国际认可的首席研究人员Drs的共同判决的协作计划。 VSMC的转录监管专家Michael S. Parmacek和Notch信号领域的领导者Warren S. Pear。 候选人将共同利用这些实验室的智力和专有资源，并由杰出医师和科学家的咨询委员会进一步指导。 参加教学课程和研究研讨会将增强该计划的教育成功。 研究计划集中在Notch信号在VSMC的分化和功能中的作用。 这些细胞具有独特的能力，可以将其表型从收缩物改变为响应血管损伤和血管增生性疾病的环境而改变。 Notch信号传导是细胞分化，增殖和细胞凋亡的描述性的调节剂，并且在某些Notch信号传导成分缺乏的动物表现出干扰的血管发育和稳态。 初步研究表明，Notch信号传导调节VSMC特异性基因表达，导致假设Notch信号在VSMC的表型调节中具有重要作用。 因此，该建议的具体目的是（1）确定Notch信号诱导的平滑肌基因表达的分子基础； （2）确定在已建立的SMC分化系统和成熟VSMC中的Notch信号传导失调的影响； （3）确定抑制小鼠中抑制SMC特异性RBP-JK依赖性凹槽信号的效果。 分子心脏病学研究中心和宾夕法尼亚大学艾布拉姆森癌症中心提供广泛的资源，合作，核心设施和知识专业知识。 因此，这是候选人获得指导培训的理想环境，以作为医师科学家独立职业。 （抽象的结尾）