The Chemokine System in Collateral Artery Formation

描述（由申请人提供）： 我的目标是成为一名学术性的血管外科医生， 他在实验室工作，并在大学教授血管外科。在这 根据这项建议，我已经确定了专家导师，并概述了学习课程 这将加强我的研究技能，特别是在以下领域： 免疫学我的研究目标是了解 侧支动脉形成侧支动脉的形成 动脉粥样硬化引起的“旁路”动脉阻塞发生在所有患者中， 但程度不同。了解侧支动脉的机制 形成可能导致新的主要和辅助治疗， 动脉粥样硬化我的长期目标是了解 趋化因子系统在侧支动脉形成中的作用我们假设的核心是 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）具有不同化学引诱物性质的趋化因子将 影响炎症浸润的数量和性质， 血管闭塞后局部细胞因子/趋化因子谱和2）单核细胞 募集是侧支动脉形成的重要决定因素。到 为了验证我们的假设，我们在初步研究中开发了一种小鼠后肢， 肢体缺血模型，并证明局部输注MCPA在 动脉闭塞部位与血流增加相关， 与生理盐水相比。我们还发现， 与正常的、未切除的相比， 控制腿为了确定血管与血管之间的关系， 重塑、趋化因子系统和免疫/炎症细胞的性质 在血管闭塞后招募，我们提出了两个具体目标。在 具体目标#1，我们将通过注入 具有不同化学引诱物性质的趋化因子：对单核细胞特异， 中性粒细胞和淋巴细胞，以确定这种改变的免疫 对侧支动脉形成的反应。在第二个具体目标中，我们将 使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（CCR 2）及其配体MCPA。中概述的实验 这个建议是创新的，因为他们采用了我们的鼠标后， 肢体缺血模型，并利用基因敲除的力量。的 这项研究的意义在于更好地了解这些机制 侧支动脉形成的可能导致设计新的主要或 动脉粥样硬化闭塞性疾病的辅助治疗，从而减少 心肌梗塞和截肢的死亡率和残疾率。这些 在导师的指导下， 这一建议中的研讨会将大大拓宽我的科学 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.