Molecular Mechanism of Disturbed Flow in Arterial Stiffening

描述(申请人提供)：这个临床医生科学家职业发展奖的目标是促进我转变为一名独立的临床医生科学家，拥有先进的知识和能力，并致力于研究基质细胞相互作用在动脉病理重塑中的关键作用。我的培训计划包括一项有指导的研究计划，该计划由一个整合的指导团队提供指导，该团队有一位导师Jo Hanjoong博士；两位共同导师：Allan Kirk医学博士；Bob Taylor医学博士；以及两位外部顾问：唐·吉登斯(佐治亚理工学院博士)和Scott Berceli(佛罗里达大学博士)。动脉硬化独立地增加患者的死亡率，动脉僵硬开始并加速。 动脉粥样硬化的发展。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，我已经确定开发动脉僵硬的治疗策略是我的患者的重要临床需求。我最近发现，紊乱的血流促进了健康小鼠的动脉硬化。初步数据表明，凝血酶敏感蛋白-1(THBS-1)是临床上可改变的动脉硬化的靶点，对血流紊乱作出反应。这一建议决定了THBS-1在动脉僵硬中的作用。我的中心假设是，血流紊乱增加了内皮细胞THBS-1的表达，从而通过转化生长因子-1促进动脉僵硬。依赖和独立的路径。该项目将通过复杂的体外和体内扰动流动模型来识别和测试与动脉僵硬有关的分子机制。我将把这项工作的重点放在利用尖端技术识别血管内皮细胞对扰动血流的反应，以及随后导致动脉硬化的血管壁生物学变化。 具有功能测试的得失。重要的是，确定的通路将被战略性地抑制，以减少动脉硬化。这项工作将提供必要的保护时间和资源，以在该领域产生重要的科学贡献，并为我在以患者为导向的科学研究领域的可持续职业生涯建立我的转化性研究实验室。

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-? 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.