For the past 14 years, our laboratory has been at the forefront of studies investigating the role ofinflammation in vascular injury and repair. Adhesive interactions between vascular cells orchestrate thisinflammatory response. During the period of this grant (years 11-14), we have continued to focus on theleukocyte integrin Mac-1 (aMPa. CD11b/CD18), identifying this adhesive receptor as a critical moleculardeterminant of leukocyte recruitment and signaling. Our laboratory first reported the interaction betweenMac-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 establishedthat leukocyte engagement of platelet GP Iba via Mac-1 is critical for vascular injury and repair, and havemade important new discoveries that the Mac-1-GP Iba interaction broadly regulates inflammation in modelsof thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis. Further, the signaling capacity of Mac-1was 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 observationsreveal novel information as to how leukocytes are recruited at sites of vascular injury and how integrins areregulated and initiate 'outside-in' signals, suggesting new opportunities for manipulation of integrin functionin vivo. These findings are the basis for this MERIT extension application. The central hypothesis of thisproposal Is that the interaction of leukocyte Mac-1 with platelet GP Iba is broadly required forinflammation and initiates pro-inflammatory and pro-thrombotic signals that promote diversedisease processes. The overall objective of this proposal is to define the role of the Mac-1-GP Ibainteraction in inflammation and thrombosis.
Our specific aims are: (1) To define the physical determinants ofthe 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 thedynamic process of thrombosis; and (4) To determine the effect of disrupting Mac-1-GP Iba on diversedisease processes, including models of atherosclerosis, arthritis, and multiple sclerosis. Because leukocyte-platelet interactions broadly regulate inflammation, understanding the molecular machinery of this cellularcomplex will provide important insights for developing new therapies directed at inflammatory diseases,including atherosclerosis, thrombosis, vasculitis, arthritis, and multiple sclerosis.

Public Health Relevance

We discovered that the interaction between leukocyte integrin Mac-1 and platelet GP Iba is critical forvascular injury and repair and now provide evidence that the Mac-1-GP Iba interaction broadly regulatesinflammation in diverse disease processes. The results of these studies will provide important insights fordeveloping new therapies directed at inflammatory diseases, including atherosclerosis, thrombosis,vasculitis, arthritis, and multiple sclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Fleg, Jerome
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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