The Chemokine System in Collateral Artery Formation

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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.