LKLF and vascular responses to hemodynamic shear in vivo

LKLF 和血管对体内血流动力学剪切的反应

基本信息

批准号：
7458614
负责人：
JOHN LEE
金额：
$ 8.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-27 至 2009-01-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458614
关键词：
Adult Alleles Anti-Inflammatory Agents Anti-inflammatory Antibodies Aorta Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Biological Biology Blood Vessels Blood flow Bos taurus Caliber Cardiology Cattle Cells Clinical Research Collaborations Condition Core Facility Cultured Cells Development Doctor of Medicine Elements Embryo Endothelial Cells Environment Functional disorder Gene Expression Gene Targeting Hemorrhage Human Indium Inflammation International Investigation Lead Lesion Lipids Liquid substance Mechanics Mediating Mediator of activation protein Mentorship Messenger RNA Molecular Molecular Genetics Morphology Mus Pathogenesis Pathologic Patients Pennsylvania Physicians Physiological Play Predisposition Prevention Proteins Research Research Personnel Research Training Role Rupture Sampling Scientist Severities Site Testing Thinking Training Programs Transfection Tunica Media Universities Vascular Cell Adhesion Molecule-1 Vascular Diseases Vascular Endothelium career clinically significant cytokine design hemodynamics in vivo lung Kruppel-like factor mature animal novel therapeutics programs promoter research study response therapeutic target tool transcription factor vasculogenesis

项目摘要

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.

描述（由申请人提供）：该建议描述了一项为期5年的研究和培训计划，旨在研究血管内皮如何感应局部血液动力学环境并介导适应性或病理反应。临床研究表明，在暴露于湍流（低剪切）血液的脉管系统的区域中，动脉粥样硬化病变倾向于发展。高剪切的区域往往受到保护。阐明局部血液动力学疾病如何影响血管生物学反应可能导致在治疗和预防血管疾病（例如动脉粥样硬化）方面的重要进展。该提议的中心假设是最近发现的剪切响应转录因子LKLF在调节血管剪切的血管反应中起着至关重要的作用。 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功能并增加对动脉粥样硬化的敏感性和严重性。该研究计划还旨在为候选人提供出色的研究培训和指导，以期过渡到独立调查的医生科学家。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）的马克·卡恩（Mark L. Kahn）监督。 Kahn博士是血管发展和病理学方面的国际认可的专家。 MCRC由M.D. Jonathon A. Epstein和M.D. M.D.的Michael S. Parmacek共同执导，在几乎所有方面的血管生物学方面都提供了广泛的合作机会，核心设施和知识专业知识。动脉粥样硬化研究将与丹尼尔·S·拉德（Daniel S.