This renewal application proposes studies focused on the structure and function of the two beta3 integrins, alphallbbeta3 and alphaVbeta3. The target cells for analysis are platelets, endothelial cells and bone marrow derived cells. These cells are all exposed to blood and the functions of their integrins must be tightly regulated to prevent uncontrolled binding of blood-borne ligands to the integrins. Analyses will be performed to define the molecular mechanisms, which regulate the functions of the integrins and govern their contribution to the adhesive and migratory properties of these cells. The information derived from these studies will, in turn, provide insights into the complex and biologically important responses of these cells, including platelet aggregation, thrombosis, cell homing and angiogenesis. The Program consists of four projects, each directed by an independent and productive faculty member in the Department of Molecular Cardiology at the Cleveland Clinic. Dr. Edward Plow, Ph.D., will serve as Program Director and lead Project 1. This project deals with the mechanism by which specific binding partners of alphallbbeta3 and alphaVbeta3, the Kindlins and Fyn, regulate the bidirectional signaling across the integrins. In Project 2;Dr. Jun Qin will use high resolution structural approaches to determine the long sought-after structure of the heterodimeric transmembrane domains of the beta3 integrins and examine how the function of talin is regulated to induce integrin activation. In Project 3, Dr. Eugene Podrez will determine how the scavenger receptor SR-BI controls the functional activity of alphallbbeta3 in platelets, thereby providing a direct link between lipoprotein metabolism and thrombosis. Dr. Tatiana Byzova leads Project 4, which focuses on the mechanisms by which beta3 integrin regulates angiogenesis with a specific emphasis on its role in recruitment of bone marrow derived cells to sites of new blood vessel formation. Three Cores, Administrative, Cell Culture and Protein Expression, and In Vivo, provide infrastructure support. A theme which transcends all four projects is the bi-directional signaling across the beta3 integrins. The studies span from structural mechanisms to intact cells and ultimately to in vivo models to test hypotheses in a biological setting and provide comprehensive insights into responses mediated by the beta3 integrins. Cementing the Program together is the cohesive focus on a common theme, the beta{3} integrins;multiple collaborations among the Projects;and a common objective of the investigators to resolve the structural and biological mechanisms that regulate the functions of the beta B{3} integrins.

Public Health Relevance

It is well established that molecules on the surface of cells determine how they participate in biological processes. This application focuses on a particular set of molecules, the beta3 integrins. By understanding how the beta3 integrins work, we will gain insights into how cells either cause or protect us from disease, and we may then be able to design drugs to treat and prevent heart attacks, strokes and cancer, the leading causes of death in the United States.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL073311-09
Application #
8260300
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Sarkar, Rita
Project Start
2003-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$1,937,388
Indirect Cost
$703,383
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Zimman, Alejandro; Titz, Bjoern; Komisopoulou, Evangelia et al. (2014) Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin. PLoS One 9:e84488
Plow, Edward F; Das, Mitali (2014) Rising like the phoenix? Arterioscler Thromb Vasc Biol 34:2182-3
Sossey-Alaoui, Khalid; Pluskota, Elzbieta; Davuluri, Gangarao et al. (2014) Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis. FASEB J 28:2260-71
Soloviev, Dmitry A; Hazen, Stanley L; Szpak, Dorota et al. (2014) Dual role of the leukocyte integrin ?M?2 in angiogenesis. J Immunol 193:4712-21
Das, Mitali; Subbayya Ithychanda, Sujay; Qin, Jun et al. (2014) Mechanisms of talin-dependent integrin signaling and crosstalk. Biochim Biophys Acta 1838:579-88
Davuluri, Gangarao; Augoff, Katarzyna; Schiemann, William P et al. (2014) WAVE3-NF?B interplay is essential for the survival and invasion of cancer cells. PLoS One 9:e110627
Plow, Edward F; Meller, Julia; Byzova, Tatiana V (2014) Integrin function in vascular biology: a view from 2013. Curr Opin Hematol 21:241-7
Gao, Detao; Willard, Belinda; Podrez, Eugene A (2014) Analysis of covalent modifications of proteins by oxidized phospholipids using a novel method of peptide enrichment. Anal Chem 86:1254-62
Yang, Jun; Zhu, Liang; Zhang, Hao et al. (2014) Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. Nat Commun 5:5880
Kerr, B A; McCabe, N P; Feng, W et al. (2013) Platelets govern pre-metastatic tumor communication to bone. Oncogene 32:4319-24

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