LKLF and vascular responses to hemodynamic shear in vivo

描述(由申请人提供)： 这项建议描述了一项为期5年的研究和培训计划，旨在调查血管内皮细胞如何感知局部血流动力学环境，并调节适应性或病理反应。临床研究表明，动脉粥样硬化病变往往发生在暴露于湍流(低切变)血流的血管系统区域。高剪切率的区域往往受到保护。阐明局部血流动力学条件如何影响血管生物反应可能会在血管疾病的治疗和预防方面取得重要进展，如动脉粥样硬化。这一建议的中心假设是，最近发现的剪切反应转录因子LKLF在调节血管对血流动力学剪切的反应中发挥关键作用。该提案中概述的具体目标将通过以下方式来验证这一假说：(1)确认LKLF在体外的剪切反应性，并确定LKLF启动子中的剪切反应元件；(2)确定LKLF是否在体内受到血流动力学剪切的类似调节；以及(3)确定LKLF在小鼠成年血管中的缺失是否会导致正常血管功能丧失，并增加动脉粥样硬化的易感性和严重性。 这项研究计划还旨在为候选人在过渡到作为医生-科学家的独立研究职业生涯期间提供出色的研究培训和指导。该培训计划将由宾夕法尼亚大学分子心脏病学研究中心(MCRC)的医学博士马克·L·卡恩负责监督。卡恩博士是国际公认的血管发育和病理生物学专家。MCRC由医学博士乔纳森·A·爱泼斯坦和医学博士迈克尔·S·帕马切克共同指导，在血管生物学的几乎所有方面提供广泛的合作机会、核心设施和智力专长。动脉粥样硬化研究将与丹尼尔·S·雷德医学博士合作进行，丹尼尔·S·雷德是脂类生物学和动脉粥样硬化发病机制领域的国际领先者。

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.