Function of Notch Signaling in Vascular Smooth Muscle

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，旨在发展血管生物学候选人的学术生涯。 研究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。 建议的活动依赖于两个国际公认的主要研究者，迈克尔S。Parmacek和Warren S. Pear，Notch信号领域的领导者。 候选人将利用这些实验室的知识和专有资源，并由杰出的医生和科学家组成的咨询委员会提供进一步指导。 参与教学课程和研究研讨会将提高该计划的教育成功。 该研究计划集中在Notch信号在VSMCs分化和功能中的作用。 这些细胞具有独特的能力，改变其表型从收缩到增殖活性，以响应血管损伤和血管增生性疾病的设置。 Notch信号传导是细胞分化、增殖和凋亡的充分描述的调节剂，并且在选择的Notch信号传导组分中缺陷的动物显示破坏的血管发育和稳态。 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表型调控中起重要作用的假设。 因此，本提案的具体目的是（1）确定Notch信号传导诱导的平滑肌基因表达的分子基础;（2）确定Notch信号传导失调在已建立的SMC分化系统和成熟VSMC中的影响;以及（3）确定抑制小鼠中SMC特异性、RBP-Jk依赖性Notch信号传导的作用。 分子心脏病学研究中心和宾夕法尼亚大学的艾布拉姆森癌症中心提供广泛的资源，合作，核心设施和知识专长。 因此，这是一个理想的设置为候选人获得指导培训走向独立的职业生涯作为一个医生，科学家。 (End摘要）

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)