Inflammation plays an essential role in vascular injury in atherosclerosis and restenosis. Adhesive interactions between vascular cells orchestrate this inflammatory response. During the period of this grant (years 6-10), we have continued to focus on the leukocyte integrin Mac-1 (aM?2, 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 we have now determined the molecular basis of GP Iba recognition, identifying the P201-K217 sequence within the aMl-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 performed a pilot study indicating that disruption of Mac-1-GP Iba prevents myocardial infarction and prolongs survival in Dahl salt-sensitive rats transgenic for human CETP. Further, the signaling capacity of Mac-1 was explored and we found that Mac-1 recruits an IL-1 receptor-like signaling cascade to induce NF-?B activity. Using a differential display strategy, we cloned a novel forkhead transcription factor, Foxp1, 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 renewal application. The central hypotheses of this proposal are that the interaction of leukocyte Mac-1 with platelet GP Iba mediates leukocyte recruitment after vascular injury, and that Mac-1 promotes pro-inflammatory and pro-thrombotic signals that promote atherogenesis, plaque rupture, thrombosis, and myocardial infarction. The overall objective of this proposal is to define the role of Mac-1-mediated inflammation in atherothrombosis.
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 investigate the role of Mac-1-GP Iba in platelet signaling and thrombosis;and (3) To determine the effect of disrupting Mac-1-GP Iba on plaque rupture, thrombosis, and survival. The experiments outlined in this proposal should clarify the role of Mac-1-GP Iba in atherothrombosis. Because leukocyte-platelet interactions represent an important linkage between inflammation, atherogenesis, and thrombosis, understanding the molecular machinery of this cellular complex will provide insights necessary to develop strategies for modulating vascular injury in the initiation, progression, and clinical complications of atherosclerosis.
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