Vascular cell adhesive interactions are important in health and diseases ranging from thrombosis and atherosclerosis to the vasculitides and cancer. Adhesion molecules including integrins, and signaling molecules including focal adhesion kinase (FAK) and immune receptors, are key in all of these processes, and are important targets of drugs currently approved and under development. This Program integrates studies at the atomic and cellular level on cell adhesion and signaling in the vasculature, with the overall aim of accelerating both the acquisition of new knowledge and the development of drugs to treat disease. It ties together a group of investigators with a long history of collaboration and interaction in the Harvard Medical Longwood Area. The investigators have expertise in a wide range of structural biology techniques including crystallography, EM, and NMR, enabling a multidisciplinary approach to solving important biological problems. Furthermore, expertise includes the extracellular, membrane, and cytoplasmic environments. The interactions between investigators with expertise in different structural techniques and different cellular environments provide important synergies between the projects in understanding signaling in the outside-in and inside-out directions across the plasma membrane. Project 1 (Springer) examines the structure and mechanism of activation of aIphalB3, its complexes with small molecules and macromolecules including fibrinogen and Del-1, and the structural basis for immune thrombocytopenic purpura. Project 2 (Springer) focuses on the molecular basis for rolling and firm adhesion through interaction of alpha4B1 and alpha4B7 integrins with ligands MAdCAM-1 and VCAM-1, and complexes with candidate therapeutic antibodies and small molecules. Project 3 (Wang) defines the structural basis for binding of leukocyte integrin aM and aX I domains to ligands C3bi, ICAM-1, and Del-1. Project 5 (Chou) defines the membrane-embedded triad structures of two archetypal members of the immune receptor family, (DAP12)2(NKG2C)1 and sigma2(NKp46)1. Project 6 (Eck) examines signaling at focal adhesions and explores activation of the tyrosine kinase of FAK by phosphatidylinositol phosphates through use of structures, cell biology, and small molecules. Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG.

Public Health Relevance

This program project brings together investigators with different expertise, to achieve synergy in tackling problems in vascular diseases. The investigators are particularly good in determining structures of molecules on the surface of cells and just underneath the surface, and their complexes with drugs. The project will accelerate development of drugs to treat bleeding disorders, thrombosis, vascular autoimmune disease, atherosclerosis, and cancer.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL103526-05
Application #
8695444
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
Kindzelski, Andrei L
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Springer, Timothy A (2014) von Willebrand factor, Jedi knight of the bloodstream. Blood 124:1412-25
Liu, Ying; Zhang, Yan; Wang, Jia-Huai (2014) Crystal structure of human Ankyrin G death domain. Proteins 82:3476-82
Blenner, Mark A; Dong, Xianchi; Springer, Timothy A (2014) Structural basis of regulation of von Willebrand factor binding to glycoprotein Ib. J Biol Chem 289:5565-79
OuYang, Bo; Chou, James J (2014) The minimalist architectures of viroporins and their therapeutic implications. Biochim Biophys Acta 1838:1058-67
Yu, Yamei; Schurpf, Thomas; Springer, Timothy A (2013) How natalizumab binds and antagonizes *4 integrins. J Biol Chem 288:32314-25
Yu, Yamei; Zhu, Jianghai; Huang, Po-Ssu et al. (2013) Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop. J Biol Chem 288:6284-94
Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A (2013) Complete integrin headpiece opening in eight steps. J Cell Biol 201:1053-68
Wang, Rui; Zhu, Jianghai; Dong, Xianchi et al. (2012) GARP regulates the bioavailability and activation of TGFýý. Mol Biol Cell 23:1129-39
Eng, Edward T; Smagghe, Benoit J; Walz, Thomas et al. (2011) Intact alphaIIbbeta3 integrin is extended after activation as measured by solution X-ray scattering and electron microscopy. J Biol Chem 286:35218-26