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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL057506-17
Application #
8477064
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fleg, Jerome
Project Start
1997-07-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
17
Fiscal Year
2013
Total Cost
$402,550
Indirect Cost
$146,149
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Plow, Edward F; Wang, Yunmei; Simon, Daniel I (2018) The search for new antithrombotic mechanisms and therapies that may spare hemostasis. Blood 131:1899-1902
Wang, Yunmei; Gao, Huiyun; Shi, Can et al. (2017) Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIb?. Nat Commun 8:15559
Wang, Yunmei; Gao, Huiyun; Kessinger, Chase W et al. (2017) Myeloid-related protein-14 regulates deep vein thrombosis. JCI Insight 2:
Swindell, William R; Xing, Xianying; Fritz, Yi et al. (2016) Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis. Oncotarget 7:35535-35551
Zidar, David A; Mudd, Joseph C; Juchnowski, Steven et al. (2016) Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes. Arterioscler Thromb Vasc Biol 36:389-97
Wang, Yunmei; Golden, Jackelyn B; Fritz, Yi et al. (2016) Interleukin 6 regulates psoriasiform inflammation-associated thrombosis. JCI Insight 1:e89384
Kereiakes, Dean J; Yeh, Robert W; Massaro, Joseph M et al. (2015) Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial. JAMA 313:1113-21
Oliveira, Guilherme H; Al-Kindi, Sadeer G; ElAmm, Chantal et al. (2015) Platelet inhibition with ticagrelor for left ventricular assist device thrombosis. Circ Heart Fail 8:649-51
Kayima, James; Nyakoojo, Wilson; Nakanjako, Damalie et al. (2015) Acute Spontaneous Coronary Artery Thrombosis as Initial Presentation of HIV Infection in a Young Man. Case Rep Cardiol 2015:342348
Golden, Jackelyn B; Wang, Yunmei; Fritz, Yi et al. (2015) Chronic, not acute, skin-specific inflammation promotes thrombosis in psoriasis murine models. J Transl Med 13:382

Showing the most recent 10 out of 57 publications