The Chemokine System in Collateral Artery Formation

描述(由申请人提供)： 我的目标是成为一名有独立研究的学术血管外科医生 实验室，在大学教授血管外科学。在这 建议，我已经确定了专家导师，并概述了学习过程 这应该会增强我的研究技能，特别是在 免疫学。我的研究目标是了解心力衰竭的基本机制。 侧支动脉形成。形成至自然的侧支动脉 动脉粥样硬化引起的“搭桥”动脉阻塞在所有患者中都会发生， 但程度不同。对侧支循环机制的认识 形成可能导致新的初级和辅助治疗 动脉硬化。我的长期目标是了解 侧支动脉形成中的趋化因子系统。我们假设的核心是 趋化因子系统影响体内的时间和空间模式 急性血管闭塞后的炎症/免疫反应。我们 假设1)具有不同趋化特性的趋化因子将 影响炎性浸润物的数量和性质以及 血管闭塞后局部细胞因子/趋化因子的变化与2)单核细胞 募集是侧支动脉形成的重要决定因素。至 检验我们的假设，我们已经在初步研究中培育出一只小鼠后 肢体缺血模型，并证明局部注射MCPA在 动脉闭塞的部位与血流量增加有关，因为 与生理盐水输注相比。我们还表明，炎症性 与正常的未切除的小腿相比，细胞被吸引到缺血的小腿上 控制腿。要确定血管之间的关系 重塑、趋化因子系统与免疫/炎症细胞的性质 在血管闭塞后招募，我们提出了两个具体的目标。在……里面 具体目标#1，我们将通过输注改变炎症浸润物 具有不同趋化特性的趋化因子：专用于单核细胞， 中性粒细胞和淋巴细胞来确定这种改变的免疫效果 对侧支动脉形成的反应。在第二个具体目标中，我们将 用小鼠测定单核细胞对侧支动脉形成的影响 严重损害单核细胞募集的小鼠，即缺乏CC的小鼠 趋化因子受体2(CCR2)及其配体MCPA。中概述的实验 这个建议很有创意，因为他们利用了我们的老鼠后腿 建立肢体缺血模型，并利用基因敲除的力量。这个 研究的意义在于更好地了解其作用机制 侧支动脉形成的研究可能导致设计新的原发或 动脉粥样硬化性闭塞症的辅助治疗，从而减少 心肌梗死和截肢的死亡率和致残率。这些 调查，在我的导师的指导下，结合课程 这个提案中的研讨会将极大地拓宽我的科学 经验让我成为一名独立的科学家。

DESCRIPTION (provided by applicant): My goal is to be an academic vascular surgeon who has an independent research laboratory and teaches vascular surgery in a university setting. In this proposal, I have identified expert mentors and outlined a course of study which should strengthen my research skills, particularly in the area of immunology. My research goal is to understand the basic mechanisms of collateral artery formation. Formation of collateral arteries to naturally "bypass" arterial obstructions from atherosclerosis occurs in all patients, but to a variable degree. Understanding the mechanisms of collateral artery formation could lead to new primary and adjuvant treatments for atherosclerosis. My long-range goal is to understand the influence of the chemokine system in collateral artery formation. Central to our hypothesis is that the chemokine system influences the in vivo temporal and spatial pattern of the inflammatory/immune response following acute vascular occlusion. We hypothesize that 1) chemokines with different chemoattractant properties will affect the quantity and character of the inflammatory infiltrate as well as local cytokine/chemokine profiles after vascular occlusion and 2) monocyte recruitment is an important determinant of collateral artery formation. To test our hypothesis, we have in preliminary studies developed a mouse hind limb model of ischemia and demonstrated that local infusion of MCPA at the site of arterial occlusion is associated with an increase in blood flow as compared to normal saline infusion. We have also shown that inflammatory cells are attracted to the ischemic leg, as compared to the normal, non-excised control leg. To determine the relationship between vascular remodeling, chemokine system and the nature of the immune/inflammatory cells recruited after vascular occlusion, we have proposed two specific aims. In the specific aim #1, we will alter the inflammatory infiltrate by infusing chemokines with different chemoattractant properties: specific for monocytes, neutrophils and lymphocytes to determine the effect of this altered immune response on collateral artery formation. In the second specific aim, we will determine the influence of monocytes on collateral artery formation using mice that have severely impaired monocyte recruitment, i.e. mice lacking the CC chemokine receptor 2 (CCR2) and its ligand, MCPA. The experiments outlined in this proposal are innovative because they employ the use of our mouse hind limb ischemia model and utilize the power of genetic knockouts. The significance of the research is that a better understanding of the mechanisms of collateral artery formation could lead to the design of novel primary or adjuvant treatments for atherosclerotic occlusive disease and thereby decrease death and disability rates from myocardial infarction and amputations. These investigations, under the guidance of my mentors and coupled with the courses and seminars in this proposal will substantially broaden my scientific experience to allow me to become an independent scientist.