BASEMENT MEMBRANE SELF-ASSEMBLY AND STRUCTURE

Summary

Principal Investigator: PETER DANA YURCHENCO
Abstract: DESCRIPTION (provided by applicant): Basement membranes (BMs) are cell-adhesive scaffolds and agonists that are required for tissue growth, differentiation and adult functions. Elucidation of the mechanisms of BM assembly. Structure and functions is critical to understand the pathogenesis of diseases of kidney, nerve and other organs, to develop structure-correcting therapies, and to engineer biomaterials with BM properties for tissue repair. Our analysis of the role of BMs in different cell and organ culture systems has revealed that laminins adhere to cells through sulfated glycolipids, initiating BM assembly by polymerizing and binding to nidogen, type IV collagen, and proteoglycans. The assembling scaffold binds to, recruits, and activates integrins and receptor kinases through tethered growth factors, and recruits and anchors to dystroglycan, serving as a function-integrating signaling platform. The current proposal is to determine how a coordination of BM domains acts to drive complex cell and tissue functions. It seeks to determine if cell polarization depends upon laminin- initiated organization of the basal cell surfaces, if b1-integrin activity depends on a coding or summation of ligand binding, if integrins act in concert with growth factors to drive differentiation, which integrin-ligand interactions are critical, and if receptor mediated signaling is modulated by the inherent structur of the BM as well as ligand density and composition. These questions will be studied in Schwann cells and renal collecting duct epithelial models whose functions are initiated by BM-assembly mediated by a library of engineered laminins and other components. The proposal also seeks to characterize key sequences involved in laminin self-assembly, a key process of BM-assembly previously discovered by the P.I. Innovation lies in the treatment of BMs as integrated signaling platforms rather than as a simple collection of ligands, in the refinement of structure-function model that allows systematic testing of hypotheses, and in the approach of dissecting integrated functions at a molecular level by inducing BM assembly and functions with engineered proteins in both simple cell and complex tissues models. Aim I. Mechanisms of BM induction of Schwann cell polarization and myelination: We will determine the contributions of the different laminin isoforms that depend on their unique domain activities, distinguish integrin from growth-factor contributions, and determine the differential role of ligands, and BM scaffold structure. Aim II. Laminin induction of renal epithelial BM, polarity and functions. The role of BM in inducing cell polarity will be examined in mouse renal ureteric bud and collecting duct cells grown in collagen gel cultures. Aim III. Functions of laminin LN and LE domains. Laminin polymerization requires formation of Lm[unreadable]LN, Lm[unreadable]LN and Lm[unreadable]LN complexes. Lm[unreadable]LN also adheres to cell surfaces. We will explore interacting sequences in LN and LE domains, dissect to role of cell adhesion, and evaluate Pierson syndrome laminin [unreadable]2LN domain mutations.
Funding Period: 1986-01-01 - 2017-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Cdc42 is crucial for the establishment of epithelial polarity during early mammalian development
    Xunwei Wu
    University of Copenhagen, Institute of Molecular Pathology, Copenhagen, Denmark
    Dev Dyn 236:2767-78. 2007
  2. pmc α6β1 and α7β1 integrins are required in Schwann cells to sort axons
    Marta Pellegatta
    San Raffaele Scientific Institute, Milano 20132, Italy, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, New York 14203, Development and Stem Cells Program, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7104, Institut National de la Santé et de la Recherche Médicale U964, Universite de Strasbourg, Illkirch 67404, France, Department of Medicine, Children s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom, and Robert Wood Johnson Medical School, Piscataway, New Jersey, New Jersey 08854
    J Neurosci 33:17995-8007. 2013

Detail Information

Publications2

  1. ncbi Cdc42 is crucial for the establishment of epithelial polarity during early mammalian development
    Xunwei Wu
    University of Copenhagen, Institute of Molecular Pathology, Copenhagen, Denmark
    Dev Dyn 236:2767-78. 2007
    ..Finally, aggregation experiments with endodermal cell lines suggested that Cdc42 might affect formation of adherens and tight junctions by PKCzeta-dependent regulation of the protein levels of p120 catenin and E-cadherin...
  2. pmc α6β1 and α7β1 integrins are required in Schwann cells to sort axons
    Marta Pellegatta
    San Raffaele Scientific Institute, Milano 20132, Italy, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, New York 14203, Development and Stem Cells Program, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7104, Institut National de la Santé et de la Recherche Médicale U964, Universite de Strasbourg, Illkirch 67404, France, Department of Medicine, Children s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom, and Robert Wood Johnson Medical School, Piscataway, New Jersey, New Jersey 08854
    J Neurosci 33:17995-8007. 2013
    ....

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  3. PAR-1b in Integrin Localization and Laminin-111 Assembly in the Salivary Gland
    ELISE GERVAIS; Fiscal Year: 2013
    ....
  4. Genomics for Transplantation: Discovery and Biomarkers
    Daniel R Salomon; Fiscal Year: 2013
    ..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
  5. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  6. Innate/Adaptive Immune Interactions in Gut Inflammation
    Sergio A Lira; Fiscal Year: 2013
    ..Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome. ..
  7. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013
    ..The 4DB Center will also serve to disseminate information, education, and training to a new generation of cancer physicists;a generation that will implement the power of physics to conquer the problems of cancer. ..
  8. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  9. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  10. The Coding, Decoding, Transfer, and Translation of Information in Cancer
    THOMAS V O'HALLORAN; Fiscal Year: 2013
    ..abstract_text> ..
  11. Center for Excellence in Diabetes and Obesity Research
    ARUNI BHATNAGAR BHATNAGAR; Fiscal Year: 2013
    ..Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide. ..
  12. LAMININS AND GLOMERULAR FILTRATION
    Jeffrey H Miner; Fiscal Year: 2013
    ..The results of these studies will provide important new insights into laminin and basement membrane biology and lead to potential therapies for human glomerular disease involving GBM defects. ..
  13. Three-dimensional Human Kidney Tissue System for Studying Renal Diseases
    Jeannine Coburn; Fiscal Year: 2013
    ..Furthermore, the model can be extended to the engineering of other organs further broadening its applications. ..
  14. MECHANISMS AND MODULATION OF ACCELLULAR HbA TOXICITY
    Joel M Friedman; Fiscal Year: 2013
    ..Olson, leader);Core D, Chemical, Cellular, And Animal Toxicity Evaluations (FDA, Alayash leader) ..
  15. Toll-Like Receptors in Systemic Autoimmune Disease
    Ann Marshak-Rothstein; Fiscal Year: 2013
    ....
  16. The exocyst in kidney development and cyst formation
    BENJAMIN CARL FOGELGREN; Fiscal Year: 2013
    ....
  17. The Laminin Receptors in Kidney Development
    Roy Zent; Fiscal Year: 2013
    ..This knowledge is fundamental to our understanding of how the renal collecting system functions and why there is an increased incidence of renal abnormalities in patients with bullous skin diseases. ..
  18. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  19. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  20. 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. ..
  21. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  22. Protein Dynamics in Enzymatic Catalysis
    Robert Callender; Fiscal Year: 2013
    ..The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. ..
  23. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  24. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  25. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  26. 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 ..