Flow responses to carotid angioplasty

描述(由申请人提供)： 这项提议是一项为期五年的培训计划，旨在发展艾伦·达迪克在血管外科的学术生涯。达迪克博士在约翰·霍普金斯医院完成了外科培训，目前是耶鲁大学医学院的外科助理教授。这一培训计划将使他能够开发、协调并将实验室结果转化为诊断和治疗动脉粥样硬化性颈动脉疾病患者的实际临床应用，并使他能够发展成为一名独立的调查员，包括准备和提交R-01提案。药理学教授、血管细胞信号和治疗计划主任、耶鲁大学/NHLBI蛋白质组学中心联席主任William Sessa博士和耶鲁大学外科教授Bauer Sumpio博士将担任讲解员，指导Dardik博士的研究和职业发展，包括指导负责任的研究行为。达迪克博士将与耶鲁大学跨系血管生物学和移植项目的资深教员密切互动，如乔丹·S·波伯博士、医学博士和博士。中风影响了2%的美国人，每年中风的发病率为70万，损失超过500亿美元；女性和少数族裔受到的影响不成比例。颈动脉血管成形术(CA)是一种快速发展的血管内治疗方法，用于治疗颈动脉狭窄，预防中风。然而，CA术后的血流动力学反应并不明确，可能会影响CA的预后和长期耐受性。申请人假设CA术后斑块破裂和内皮剥蚀直接使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，抑制细胞凋亡，最终导致血管再狭窄。这项建议将在动物模型中检查CA的反应，包括开发一种新的复杂流动的手术模型，开发MRI技术来评估血流速度分布和壁面切应力，以及使用基因敲除小鼠检查Akt的作用。SMC在体外对层流和复杂流动的直接响应将用分子生物学技术来检测。具体目的是：1.测定颈动脉成形术对血流的影响。2.检测颈动脉成形术对Akt和mTOR通路激活的影响。3.比较简单和复杂血流对SMC增殖和凋亡的影响。这份提案中获得的信息将为我们的患者提供一个合理检查和指导治疗的框架。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达迪克博士作为临床科学家建立学术生涯的潜力。这项提案试图了解血管成形术或搭桥手术等血管干预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，并将患者的痛苦降至最低。(摘要结束)

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)