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)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
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
2011-08-20
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
Xu, Shutong; Wang, Jianchuan; Wang, Jia-Huai et al. (2017) Distinct recognition of complement iC3b by integrins ?X?2 and ?M?2. Proc Natl Acad Sci U S A 114:3403-3408
Chen, Bing; Chou, James J (2017) Structure of the transmembrane domain of HIV-1 envelope glycoprotein. FEBS J 284:1171-1177
Li, Jing; Springer, Timothy A (2017) Integrin extension enables ultrasensitive regulation by cytoskeletal force. Proc Natl Acad Sci U S A 114:4685-4690
Fu, Hongxia; Jiang, Yan; Yang, Darren et al. (2017) Flow-induced elongation of von Willebrand factor precedes tension-dependent activation. Nat Commun 8:324
Piai, Alessandro; Fu, Qingshan; Dev, Jyoti et al. (2017) Optimal Bicelle Size q for Solution NMR Studies of the Protein Transmembrane Partition. Chemistry 23:1361-1367
Li, Jing; Su, Yang; Xia, Wei et al. (2017) Conformational equilibria and intrinsic affinities define integrin activation. EMBO J 36:629-645
Lin, Fu-Yang; Zhu, Jianghai; Eng, Edward T et al. (2016) ?-Subunit Binding Is Sufficient for Ligands to Open the Integrin ?IIb?3 Headpiece. J Biol Chem 291:4537-46
Fu, Qingshan; Fu, Tian-Min; Cruz, Anthony C et al. (2016) Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor. Mol Cell 61:602-613
Dev, Jyoti; Park, Donghyun; Fu, Qingshan et al. (2016) Structural basis for membrane anchoring of HIV-1 envelope spike. Science 353:172-175
Chen, Xinping; Zhao, Chunyue; Li, Xiaolong et al. (2015) Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat Chem Biol 11:19-25

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