Molecular Mechanism of Disturbed Flow in Arterial Stiffening

描述（由申请人提供）：这个临床医生科学家职业发展奖的目标是促进我过渡到一个独立的临床医生，科学家与先进的知识和能力与利基解决动脉病理重塑的基质细胞相互作用的关键作用。我的培训计划包括一个指导研究计划，该计划由一个综合指导团队提供指导，该团队有一位导师Hanjoong Jo博士;两位共同导师：Allan Kirk MD，PhD; Bob Taylor MD，PhD;以及两位外部顾问：Don Giddens，PhD（格鲁吉亚理工学院）; Scott Berceli MD，PhD（佛罗里达大学）。动脉硬化独立增加患者死亡率，动脉硬化启动并加速 动脉粥样硬化的发展。作为一名拥有细胞生物学博士学位的临床活跃的血管外科医生，我已经确定了动脉硬化治疗策略的发展是我的患者的重要临床需求。我最近发现，干扰流促进健康小鼠的动脉硬化。初步数据已经确定，凝血酶敏感蛋白-1（THBS-1）是一个临床上可改变的动脉硬化的目标，以响应干扰流。这一提议确定了THBS-1在动脉硬化中的作用。我的中心假设是，扰动流增加了THBS-1的EC表达，THBS-1通过TGF-β依赖性和非依赖性途径促进动脉硬化。该项目将通过复杂的体外和体内扰动流模型来识别和测试动脉僵硬的分子机制。我将把这项工作的重点放在确定内皮细胞对干扰流的反应和随后的血管壁生物学变化，导致动脉硬化，利用先进技术与功能测试的增益和损失。重要的是，将策略性地抑制所确定的途径以减少动脉硬化。这项工作将提供必要的保护时间和资源，以在这一领域产生重要的科学贡献，并建立我的转化研究实验室，在病人为导向的科学研究的可持续职业生涯。

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.