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（由适用提供）：这一临床科学家职业发展奖的目标是促进我向具有先进知识和能力的独立临床科学家的过渡，其利基市场涉及矩阵相互作用对动脉病理重塑的关键作用。我的培训计划包括一项指导的研究计划，并在指导者Hanjoong Jo博士的指导下进行了指导；两位合作者：Allan Kirk MD博士；鲍勃·泰勒（Bob Taylor）医学博士；和两位外部顾问：唐·吉登斯（Don Giddens），博士学位（佐治亚理工学院）；医学博士Scott Berceli（佛罗里达大学）。僵硬的动脉独立增加了患者死亡率，动脉僵硬启动并加速动脉粥样硬化的发展。作为一名具有细胞生物学博士学位的临床活跃的血管外科医生，我确定了动脉僵硬的治疗策略的发展是对患者的巨大临床需求。我最近确定，影响流动会促进健康小鼠的动脉僵硬。初步数据已将血小板传播1（THBS-1）鉴定为临床修改的动脉僵硬靶标，以应对流动障碍。提案决定了THBS-1在动脉刚度中的作用。我的中心假设是，受影响的流量增加了THBS-1的EC表达，这通过TGF-ß取决于和独立的途径促进了动脉僵硬。该项目将识别并测试与动脉刚度相关的分子机制，并具有成熟的体外和体内受影响流量的模型。我将这项工作重点放在确定对受影响流量的内皮细胞反应以及随后的血管壁生物学变化，这些变化利用尖端技术通过增益和功能测试损失而导致动脉僵硬。重要的是，确定的途径将在战略上被抑制以减少动脉僵硬。这项工作将为在该领域产生重要的科学贡献所需的受保护的时间和资源，并为患者指导的科学研究的可持续职业建立我的转化研究实验室。