Complications in atherosclerosis are the leading cause of mortality and morbidity in Western societies. The mechanisms of atherogenesis, which is hallmarked by macrophage accumulation in the plaque and subsequent foam cell formation are not fully understood. Integrin aDb2 (CD11d/CD18) is a leukocyte adhesive receptor that upregulates on inflammatory macrophages and especially on foam cells during atherogenesis. The function of this receptor in the development of inflammation is not well studied. The long term goal of this project is to understand the role of integrin aDb2 in the pathophysiology of chronic inflammation. The objective of this work is to determine the impact of integrin aDb2 on the development of atherosclerosis, focusing on both components of early atherogenesis ' macrophage accumulation and lipid deposition. The central hypothesis is that integrin aDb2 is not essential for monocyte migration to the lesions, but is critical for the retention of macrophages at the site of inflammation, and that aDb2-mediated adhesion during macrophage arrest significantly contributes to foam cell formation. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1. Determine the role of integrin aDb2 on the development of atherosclerosis. 2. Examine the contribution of integrin aDb2 to the macrophage migration from the blood stream, retention within the atherosclerotic lesion and emigration to the lymph nodes. 3. Evaluate the contribution of integrin aDb2 to foam cell formation. This proposal is innovative because the importance of high density of integrins for the retention of macrophages during the development of atherosclerosis has not been previously suggested. Therefore, the hypothesis of integrin-dependent inhibition of macrophage migration at the site of inflammation proposes a qualitatively new approach for the treatment of chronic inflammatory diseases. The contribution of the proposed research is significant because it can explain the mechanism of macrophage retention at the site of chronic inflammation and can clarify the role of integrins in the regulation of oxidized lipid deposition. This information is critical for understanding the mechanism of atherosclerotic lesion formation and may lead to new pharmacological targets for the treatment of atherosclerosis. Furthermore, better fundamental understanding of how adhesive receptors mediate cell migration and retention can be anticipated.
|Effective start/end date||07/01/2014 → 06/30/2016|