Flow responses to carotid angioplasty

描述（由申请人提供）： 该提案是一项为期五年的培训计划，旨在发展Alan Dardik在血管外科领域的学术生涯。Dardik博士在约翰霍普金斯医院完成了外科培训，目前是耶鲁大学医学院外科助理教授。该培训计划将使他能够开发，协调和翻译实验室结果，并将其转化为临床应用，用于诊断和治疗动脉粥样硬化性颈动脉疾病患者，并使他能够发展成为一名独立的研究者，包括准备和提交R-01提案。William Sessa博士，药理学教授，血管细胞信号传导和治疗项目主任，耶鲁/NHLBI蛋白质组学中心联合主任，Bauer Sumpio博士，耶鲁大学外科教授，将担任评论员，并指导Dardik博士的研究和职业发展，包括负责任的研究行为指导。Dardik博士将与耶鲁大学跨部门血管生物学和移植项目的高级教师密切互动，如Jordan S Pober，MD，PhD。中风影响2%的美国人，每年发生70万例中风，花费超过500亿美元;妇女和少数民族受到严重影响。颈动脉血管成形术（CA）是一种快速发展的血管内治疗颈动脉狭窄，预防中风。然而，CA后的血流动力学反应并不明确，可能会影响CA的结局和长期耐久性。申请人假设CA后斑块破裂和内皮剥脱直接使平滑肌细胞（SMC）暴露于复杂的动脉血流;复杂的血流直接刺激SMC Akt活性，导致SMC增殖、细胞凋亡抑制和最终血管再狭窄。该提案将在动物模型中研究对CA的反应，包括开发一种新的复杂血流手术模型，开发MRI技术以评估流速分布和壁切应力，以及使用基因敲除小鼠检查Akt的作用。本文将采用分子生物学技术研究SMC对层流和复杂流场的直接响应。具体目标是：1.确定颈动脉血管成形术对体内血流的影响。2.确定颈动脉血管成形术对Akt和mTOR通路激活的影响。3.比较简单和复杂血流对平滑肌细胞增殖和凋亡的影响。本提案中获得的信息将提供一个框架，以合理地检查和指导我们的患者的治疗。耶鲁大学的学术环境，多样化的资源和对研究的热情将最大限度地发挥Dardik博士作为临床科学家建立学术生涯的潜力。该提案旨在了解血管介入（如血管成形术或旁路手术）过早失败的复杂机制。通过开发检测异常血流模式的技术，并了解这些血流模式对平滑肌细胞的影响，我们希望开发出更持久的血管干预措施，并最大限度地减少患者的痛苦。(End摘要）

DESCRIPTION (provided by applicant): This proposal is a five-year training program for the development of Alan Dardik's academic career in Vascular Surgery. Dr. Dardik completed surgical training at the Johns Hopkins Hospital and is currently Assistant Professor of Surgery at Yale University School of Medicine. This training program will allow him to develop, coordinate, and translate laboratory findings into practical clinical applications for the diagnosis and treatment of patients with atherosclerotic carotid disease, and allow him to develop into an independent investigator including preparation and submission of an R-01 proposal. William Sessa, PhD, Professor of Pharmacology and Director of the Vascular Cell Signaling and Therapeutics Program, and Co-Director of the Yale/NHLBI Proteomics Center, and Bauer Sumpio, MD, PhD, Professor of Surgery at Yale, will serve as comentors, and guide Dr. Dardik's research and career development, including instruction in the Responsible Conduct of Research. Dr. Dardik will closely interact with senior faculty in Yale's Interdepartmental Vascular Biology and Transplant Program such as Jordan S Pober, MD, PhD. Stroke affects 2% of Americans, with an annual incidence of 700,000 strokes, and cost of over $50 billion; women and minorities are disproportionally affected. Carotid angioplasty (CA) is a rapidly evolving endovascular treatment for carotid stenosis, preventing stroke. However, the hemodynamic responses following CA are not well defined and may influence the outcome and long-term durability of CA. The applicant hypothesizes that plaque fracture and endothelial denudation after CA directly expose smooth muscle cells (SMC) to complicated arterial flow; complicated flow directly stimulates SMC Akt activity, leading to SMC proliferation, suppression of apoptosis, and ultimately vessel restenosis. This proposal will examine the response to CA in an animal model, including development of a novel surgical model of complicated flow, development of MRI techniques to assess flow velocity distribution and wall shear stress, and examination of the role of Akt using knockout mice. The response of SMC directly to laminar and complicated flow in vitro will be examined with molecular biological techniques. The specific aims are: 1. Determine the effects of carotid angioplasty on flow in vivo. 2. Determine the effects of carotid angioplasty on Akt and mTOR pathway activation. 3. Compare the effects of simple and complicated flow on SMC proliferation and apoptosis. The information obtained in this proposal will provide a framework to rationally examine and direct therapy for our patients. The academic environment, diverse resources, and enthusiasm for research at Yale will maximize the potential for Dr Dardik to establish an academic career as a clinician scientist. This proposal seeks to understand the complex mechanisms by which vascular intervention such as angioplasty or bypass surgery fail prematurely. By developing techniques to detect abnormal flow patterns and understanding the effects of these flow patterns on smooth muscle cells, we hope to develop vascular interventions that are longer-lasting and minimize patient suffering. (End of Abstract)