New treatments are needed to decrease the complications of atherosclerosis, which include death, disability, heart attack, and amputation. Notably, collateral artery formation that """"""""naturally"""""""" bypasses arterial obstructions occurs in all patients, but to a variable degree. Understanding the mechanisms of collateral artery formation and ischemic tissue necrosis could lead to new primary and adjuvant therapies for atherosclerosis. My long term research goal is to understand the basic mechanisms underlying collateral artery formation and tissue necrosis and specifically, in this application, ! will determine the influence of the immune system in collateral artery formation and tissue necrosis secondary to ischemia. Central to my hypothesis is that the recruitment and activation of inflammatory cells and the concomitant immune response influences collateral artery formation and susceptibility to tissue necrosis. I hypothesize that 1) immune differences account for their differential susceptibility to tissue necrosis in two inbred mouse strains, 2) T-cell recruitment and activation is an important determinant of susceptibility to tissue necrosis and 3) the MCP-1/CCR2 axis is an important determinant of susceptibility to tissue necrosis. Monocyte Chemoattractant Protein-1 (MCP-1) and its receptor CCR2 are important regulators of immune cell recruitment and differentiation. To test these hypotheses, I have in preliminary studies a) developed a mouse hind limb model of ischemia and have demonstrated that inbred strains of mice have differential susceptibilities to tissue necrosis; b) demonstrated that nude mice lacking T-cells and mice lacking MCP-1 or CCR2 have an increased incidence and severity of tissue necrosis as compared to wild type controls and c) shown that there is an increased recruitment of inflammatory cells to the ischemic hind limb. To test my hypothesis, I have proposed three specific aims.
In aim #1, I will identify the mechanisms underlying the differential susceptibility to tissue necrosis in two inbred strains of mice.
In aim #2, I will determine the role of T-cells and the Thl/Th2 immune response in tissue necrosis and in aim #3 I will determine the role of the MCP-1tCCR2 axis in tissue necrosis by using mice that are genetically inactivated for CCR2 and its ligand, MCP-1. The experiments outlined in this proposal are innovative because they utilize the power of genetic knockout mice in a hind limb ischemia model. I have assembled an experienced team of researchers in the diverse areas of vascular biology, immunology and physiology to test these hypotheses. The significance of this research is that a better understanding of the mechanisms of collateral artery formation and susceptibility to tissue necrosis 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.
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