MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES

Summary

Principal Investigator: Timothy A Springer
Abstract: DESCRIPTION (as provided by applicant): 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. (End of Abstract)
Funding Period: 2011-08-20 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Intact alphaIIbbeta3 integrin is extended after activation as measured by solution X-ray scattering and electron microscopy
    Edward T Eng
    Immune Disease Institute, Children s Hospital Boston, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 286:35218-26. 2011
  2. pmc The minimalist architectures of viroporins and their therapeutic implications
    Bo Ouyang
    State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
    Biochim Biophys Acta 1838:1058-67. 2014
  3. pmc How natalizumab binds and antagonizes α4 integrins
    Yamei Yu
    From the Program in Cellular and Molecular Medicine, Children s Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
    J Biol Chem 288:32314-25. 2013
  4. pmc Complete integrin headpiece opening in eight steps
    Jieqing Zhu
    Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    J Cell Biol 201:1053-68. 2013
  5. pmc Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop
    Yamei Yu
    Program in Cellular and Molecular Medicine, Children s Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 288:6284-94. 2013
  6. pmc α(V)β(3) integrin crystal structures and their functional implications
    Xianchi Dong
    Immune Disease Institute, Children s Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, United States
    Biochemistry 51:8814-28. 2012
  7. pmc Mechanisms for kinase-mediated dimerization of the epidermal growth factor receptor
    Chafen Lu
    Immune Disease Institute, Children s Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 287:38244-53. 2012
  8. pmc The RGD finger of Del-1 is a unique structural feature critical for integrin binding
    Thomas Schürpf
    Immune Disease Institute, Harvard Medical School, Boston, MA, USA
    FASEB J 26:3412-20. 2012
  9. pmc GARP regulates the bioavailability and activation of TGFβ
    Rui Wang
    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Immune Disease Institute and Children s Hospital, Boston, MA 02115, USA
    Mol Biol Cell 23:1129-39. 2012
  10. pmc A New Angle on TCR Activation
    Jia huai Wang
    Laboratory of Immunobiology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
    Immunity 35:658-60. 2011

Research Grants

  1. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
  2. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
  3. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
  4. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
  5. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  6. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  8. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
  9. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
  10. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013

Detail Information

Publications11

  1. pmc Intact alphaIIbbeta3 integrin is extended after activation as measured by solution X-ray scattering and electron microscopy
    Edward T Eng
    Immune Disease Institute, Children s Hospital Boston, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 286:35218-26. 2011
    ..The observed extension and conformational rearrangement upon activation are consistent with the extension and headpiece opening model of integrin activation...
  2. pmc The minimalist architectures of viroporins and their therapeutic implications
    Bo Ouyang
    State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
    Biochim Biophys Acta 1838:1058-67. 2014
    ..This article is part of a Special Issue entitled: Viral Membrane Proteins-Channels for Cellular Networking. ..
  3. pmc How natalizumab binds and antagonizes α4 integrins
    Yamei Yu
    From the Program in Cellular and Molecular Medicine, Children s Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
    J Biol Chem 288:32314-25. 2013
    ..Skewing away from these conserved regions of the epitopes recognized by current therapeutic function-blocking antibodies has resulted in previously unanticipated mechanisms of action. ..
  4. pmc Complete integrin headpiece opening in eight steps
    Jieqing Zhu
    Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    J Cell Biol 201:1053-68. 2013
    ..RGD concentration requirements in soaking suggested a >200-fold higher affinity after opening. The thermodynamic cycle shows how higher affinity pays the energetic cost of opening. ..
  5. pmc Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop
    Yamei Yu
    Program in Cellular and Molecular Medicine, Children s Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 288:6284-94. 2013
    ....
  6. pmc α(V)β(3) integrin crystal structures and their functional implications
    Xianchi Dong
    Immune Disease Institute, Children s Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, United States
    Biochemistry 51:8814-28. 2012
    ....
  7. pmc Mechanisms for kinase-mediated dimerization of the epidermal growth factor receptor
    Chafen Lu
    Immune Disease Institute, Children s Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 287:38244-53. 2012
    ....
  8. pmc The RGD finger of Del-1 is a unique structural feature critical for integrin binding
    Thomas Schürpf
    Immune Disease Institute, Harvard Medical School, Boston, MA, USA
    FASEB J 26:3412-20. 2012
    ..A database search for EGF domain sequences shows that this RGD finger is likely an evolutionary insertion and unique to the EGF domain of Del-1 and its homologue milk fat globule-EGF 8...
  9. pmc GARP regulates the bioavailability and activation of TGFβ
    Rui Wang
    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Immune Disease Institute and Children s Hospital, Boston, MA 02115, USA
    Mol Biol Cell 23:1129-39. 2012
    ..Our results show that GARP is a latent TGFβ-binding protein that functions in regulating the bioavailability and activation of TGFβ...
  10. pmc A New Angle on TCR Activation
    Jia huai Wang
    Laboratory of Immunobiology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
    Immunity 35:658-60. 2011
    ..Adams et al. (2011) in this issue of Immunity provide evidence that docking geometry may impact 2D binding and T cell activation...
  11. pmc Structural basis of regulation of von Willebrand factor binding to glycoprotein Ib
    Mark A Blenner
    From the Program in Cellular and Molecular Medicine, Boston Children s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
    J Biol Chem 289:5565-79. 2014
    ....

Research Grants30

  1. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  2. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
  3. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
    ..HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core ..
  4. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  5. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  6. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  8. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  9. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  10. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  11. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..