LKLF and vascular responses to hemodynamic shear in vivo

描述（由申请人提供）： 本提案描述了一项为期5年的研究和培训计划，旨在研究血管内皮细胞如何感知局部血流动力学环境并介导适应性或病理性反应。 临床研究表明，动脉粥样硬化病变倾向于在暴露于湍流（低剪切）血流的脉管系统区域中发展。高剪切区域往往受到保护。 阐明局部血流动力学条件如何影响血管生物学反应可能导致血管疾病（如动脉粥样硬化）的治疗和预防的重要进展。 这个建议的中心假设是，最近发现的剪切响应转录因子，LKLF，在调节血管血流动力学剪切反应中起着至关重要的作用。 本提案中概述的具体目标将通过以下方式检验这一假设：（1）确认LKLF离体剪切反应性并鉴定LKLF启动子中的剪切反应元件，（2）确定LKLF是否类似地受体内血流动力学剪切的调节，以及（3）确定小鼠成体血管系统中LKLF的缺失是否导致正常血管功能的丧失并增加对动脉粥样硬化的易感性和严重性。 该研究计划还旨在为候选人提供优秀的研究培训和指导，过渡到独立调查的职业生涯作为一个医生，科学家。 培训计划将由Mark L.卡恩，医学博士，分子心脏病学研究中心（MCRC）在宾夕法尼亚大学。Kahn博士是国际公认的血管发育和病理学专家。 MCRC，由Jonadia共同执导。爱泼斯坦，医学博士，迈克尔S。Parmacek，医学博士，部门负责人，提供广泛的合作机会，核心设施，并在血管生物学的几乎所有方面的知识专长。将与丹尼尔S.雷德医学博士，脂质生物学和动脉粥样硬化发病机制领域的国际领导者。

DESCRIPTION (provided by applicant): This proposal describes a 5-year research and training program designed to investigate how the vascular endothelium senses the local hemodynamic environment and mediates an adaptive or pathologic response. Clinical studies show that atherosclerotic lesions tend to develop in regions of the vasculature exposed to turbulent (low shear) blood flow. Regions of high shear tend to be protected. Elucidating how local hemodynamic conditions effect vascular biological responses may lead to important advances in the treatment and prevention of vascular diseases, such as, atherosclerosis. The central hypothesis of this proposal is that a recently discovered shear-responsive transcription factor, LKLF, plays a critical role in modulating the vascular response to hemodynamic shear. The specific aims outlined in this proposal will test this hypothesis by (1) confirming the shear-responsiveness of LKLF ex vivo and identifying shear-responsive elements in the LKLF promoter, (2) determining if LKLF is similarly regulated by hemodynamic shear in vivo, and (3) determining if loss of LKLF in murine adult vasculature causes loss of normal vascular function and increases susceptibility to and severity of atherosclerosis. This research plan is also designed to provide the candidate with outstanding research training and mentorship during transition to a career of independent investigation as a physician-scientist. The training program will be supervised by Mark L. Kahn, M.D., in the Molecular Cardiology Research Center (MCRC) at the University of Pennsylvania. Dr. Kahn is an internationally recognized expert in vascular development and pathobiology. The MCRC, co-directed by Jonathon A. Epstein, M.D., and Michael S. Parmacek, M.D., Division Chief, offers extensive collaborative opportunities, core facilities, and intellectual expertise in nearly all aspects of vascular biology. Atherosclerosis studies will be performed in collaboration with Daniel S. Rader, M.D., an international leader in the field of lipid biology and pathogenesis of atherosclerosis.