For the past 14 years, our laboratory has been at the forefront of studies investigating the role of inflammation in vascular injury and repair. Adhesive interactions between vascular cells orchestrate this inflammatory response. During the period of this grant (years 11-14), we have continued to focus on the leukocyte integrin Mac-1 (aMPa. CD11b/CD18), identifying this adhesive receptor as a critical molecular determinant of leukocyte recruitment and signaling. Our laboratory first reported the interaction between Mac-1 and its platelet counter-receptor GP Iba and determined the molecular basis of GP Iba recognition, identifying the P201-K217 sequence within the aMi-domain as the binding site for GP Iba, We established that leukocyte engagement of platelet GP Iba via Mac-1 is critical for vascular injury and repair, and have made important new discoveries that the Mac-1-GP Iba interaction broadly regulates inflammation in models of thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis. Further, the signaling capacity of Mac-1 was explored and using a differential display strategy we cloned a novel forkhead transcription factor, Foxpl, which is regulated by Mac-1 signaling and controls monocyte differentiation. Together these observations reveal novel information as to how leukocytes are recruited at sites of vascular injury and how integrins are regulated and initiate """"""""outside-in"""""""" signals, suggesting new opportunities for manipulation of integrin function in vivo. These findings are the basis for this MERIT extension application. The central hypothesis of this proposal Is that the interaction of leukocyte Mac-1 with platelet GP Iba is broadly required for inflammation and initiates pro-inflammatory and pro-thrombotic signals that promote diverse disease processes. The overall objective of this proposal is to define the role of the Mac-1-GP Iba interaction in inflammation and thrombosis.
Our specific aims are: (1) To define the physical determinants of the interactions between Mac-1-GP Iba and the nature of """"""""outside-in"""""""" signals generated by this interaction; (2) To develop a small molecule inhibitor of Mac-1-GP Iba;(3) To investigate the role of Mac-1-GP Iba in the dynamic process of thrombosis;and (4) To determine the effect of disrupting Mac-1-GP Iba on diverse disease processes, including models of atherosclerosis, arthritis, and multiple sclerosis. Because leukocyte- platelet interactions broadly regulate inflammation, understanding the molecular machinery of this cellular complex will provide important insights for developing new therapies directed at inflammatory diseases, including atherosclerosis, thrombosis, vasculitis, arthritis, and multiple sclerosis.
We discovered that the interaction between leukocyte integrin Mac-1 and platelet GP Iba is critical for vascular injury and repair and now provide evidence that the Mac-1-GP Iba interaction broadly regulates inflammation in diverse disease processes. The results of these studies will provide important insights for developing new therapies directed at inflammatory diseases, including atherosclerosis, thrombosis, vasculitis, arthritis, and multiple sclerosis.
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