Function of Notch Signaling in Vascular Smooth Muscle

描述(由申请人提供)： 这份提案描述了一项为期5年的培训计划，旨在为应聘者发展血管生物学方面的学术生涯。这项研究的重点是血管平滑肌细胞(VSMC)的分化和表型调节，重点是细胞信号在这些过程中的作用。建议的活动依赖于一项合作研究计划，该计划由两名国际公认的主要研究人员共同监督，他们是VSMCs转录调控专家Michael S.Parmacek博士和Notch信号领域的领导者Warren S.Pear博士。候选人将在由杰出医生和科学家组成的咨询委员会的进一步指导下，共同利用这些实验室的智力和专有资源。参加教学课程和研究研讨会将提高该计划的教育成功。 研究计划集中在Notch信号在VSMC分化和功能中的作用。这些细胞具有独特的能力，可以在血管损伤和血管增生性疾病的背景下，将其表型从收缩活动改变为增殖活动。Notch信号是一种众所周知的细胞分化、增殖和凋亡的调节器，缺乏选择Notch信号成分的动物表现出血管发育和动态平衡被破坏。初步研究表明，Notch信号调节VSMC特异性基因的表达，从而提出Notch信号在VSMC的表型调控中起重要作用的假说。因此，这项建议的具体目的是：(1)确定Notch信号诱导平滑肌基因表达的分子基础；(2)确定Notch信号在已建立的SMC分化系统和成熟的VSMCs中的影响；以及(3)确定抑制SMC特异性的、RBP-JK依赖的Notch信号的效果。 宾夕法尼亚大学的分子心脏病研究中心和艾布拉姆森癌症中心提供广泛的资源、合作、核心设施和智力专业知识。因此，对于应聘者来说，这是一个理想的环境，可以接受指导培训，成为一名独立的内科科学家。(摘要结束)

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)