Molecular Mechanism of Disturbed Flow in Arterial Stiffening

动脉硬化扰动血流的分子机制

基本信息

批准号：
9212681
负责人：
LUKE Packard BREWSTER
金额：
$ 16.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212681
关键词：
Address Affect Amputation Arterial Fatty Streak Arteries Atherosclerosis Award Biological Biological Models Biology Biomechanics Blood Vessels Cell Culture Techniques Cellular biology Clinical Cultured Cells Data Deposition Development Disease Doctor of Philosophy Dose Effectiveness Endothelial Cells Endothelium Event Florida Gene Targeting Genetic Transcription Goals Grant Hour In Vitro Institutes Investigation K-Series Research Career Programs Knowledge Laboratories Laboratory Research Lead Medical Mentors Mentorship Modulus Molecular Molecular Target Mus Pathologic Pathway interactions Patients Phosphorylation Physiological Process Proteins Research Resources Role Scientist Signal Pathway Signal Transduction Specimen Surgeon TGFB1 gene Techniques Technology Testing Thinness Thrombospondin 1 Time Training Programs Transforming Growth Factor beta Translational Research Universities Validation Work age related arterial stiffness atheroprotective autocrine biomechanical model career career development cell type clinically relevant hands-on learning human disease in vitro testing in vivo in vivo Model inhibitor/antagonist loss of function mortality mouse model novel paracrine public health relevance response shear stress skills targeted treatment therapeutic target therapy development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The goal of this clinician scientist career development award is to facilitate my transition into an independent clinician-scientist with advanced knowledge and capacity with a niche addressing the critical role of matricellular interactions on pathologic remodeling of arteries. My training program comprises a mentored research plan with guidance from an integrated mentoring team with a mentor, Hanjoong Jo, PhD; two co- mentors: Allan Kirk MD, PhD; Bob Taylor MD, PhD; and two external advisors: Don Giddens, PhD (Georgia Institute of Technology); Scott Berceli, MD, PhD (University of Florida). Stiffened arteries independently increase patient mortality, and arterial stiffness initiates and accelerates the development of atherosclerosis. As a clinically active vascular surgeon with a PhD in cell biology, I have identified the development of treatment strategies for arterial stiffness as a significant clinical need for my patients. I have recently identified that disturbed flow promotes arterial stiffening in healthy mice. Preliminary data has identified thrombospondin-1 (THBS-1) as a clinically modifiable target of arterial stiffening in response to disturbed flow. This proposal determines the role of THBS-1 in arterial stiffness. My central hypothesis is that disturbed flow increases EC expression of THBS-1, which promotes arterial stiffness via TGF-ß dependent and independent pathways. This project will identify and test the molecular mechanisms involved in arterial stiffness with sophisticated in vitro and in vivo models of disturbed flow. I ill focus this work on identifying the endothelial cell response to disturbed flow and the subsequent changes in vascular wall biology that lead to arterial stiffening utilizing cutting edge techniques with gain and loss of function testing. Importantly the pathways identified will be strategically inhibited to decrease arterial stiffening. This work will provide the protected time and resources necessary to generate important scientific contributions in this field and build my translational research laboratory for a sustainable career in patient-directed scientific investigation.

描述（由申请人提供）：该临床医生科学家职业发展奖的目标是促进我转变为一名具有先进知识和能力的独立临床医生科学家，并在我的培训中解决基质细胞相互作用对动脉病理重塑的关键作用。该计划包括一个由综合指导团队指导的研究计划，其中包括一位导师 Hanjoong Jo 博士；两位联合导师：Allan Kirk 医学博士、博士；以及两位外部顾问：Don； Giddens 博士（佐治亚理工学院）；Scott Berceli 博士（佛罗里达大学）。作为一名临床活跃的血管外科医生，拥有细胞生物学博士学位，我认为开发动脉硬化治疗策略是我的患者的一项重要临床需求，我最近发现血流紊乱会促进健康的动脉硬化。初步数据已确定血小板反应蛋白-1 (THBS-1) 是响应血流紊乱的动脉硬化的临床可改变靶标。我的中心假设是，血流紊乱会增加 THBS-1 的 EC 表达，从而通过 TGF-β 依赖性和独立途径促进动脉僵硬度，该项目将通过复杂的体外和体内实验来识别和测试与动脉僵硬度相关的分子机制。我将把这项工作的重点放在识别内皮细胞对血流紊乱的反应以及利用尖端技术和功能获得和丧失测试导致动脉硬化的血管壁生物学变化。重要的是，所确定的途径将被战略性地抑制，以减少动脉硬化。这项工作将为在该领域做出重要的科学贡献提供必要的受保护时间和资源，并建立我的转化研究实验室，以实现以患者为导向的科学研究的可持续职业生涯。