YEARS

2011-2016

AUTHORS

Andrea I Alford

TITLE

Functional Characterization of Thrombospondin-2 in Bone Extracellular Matrix

ABSTRACT

DESCRIPTION (provided by applicant): The objective of the 5 year career development plan outlined in this KO1 application is to foster the development of the candidate, Dr. Alford into a productive, independent investigator in the field of osteoblast cellular and extracellular matrix biology. Under the guidance of her mentors, Drs Steven A Goldstein and Renny T Franceschi, and through regular interactions with expert consultants, Stephen J. Weiss and Kurt D. Hankenson, the candidate will carry out the proposed research as a member of the Orthopaedic Research Laboratories in the Department of Orthopaedic Surgery at the University of Michigan. In the 5 year research plan proposed here, we will utilize primary MSC harvested from TSP2-null mice and their littermates in a well established in vitro model of osteoblastogenesis to test the global hypothesis that matrix-bound TSP2 makes specific contributions to osteoblast lineage progression which are dependent on the differentiation state of the cell, as well as on the unique extracellular milieu associated with matrix assembly, maturation and mineralization. Specifically, in aim 1 we will address the working hypothesis that in the context of early osteoblast-differentiation events, TSP2 promotes the assembly of a type I collagen-rich osteoblast-derived extracellular matrix, and as a result, it indirectly promotes collagen-dependent signal transduction events that are critical for osteoblast differentiation. In specific aim 2, we will address the premise that, in the context of matrix mineralization, TSP2 makes an additional unique contribution to osteoblast maturation. Specifically, we hypothesize that TSP2 is proteolytically processed to release biologically relevant fragments that affect matrix mineralization. Together, the experiments outlined in this proposal will define differentiation-stage dependent contributions that TSP2 makes to osteoblast lineage progression and matrix mineralization.

FUNDED PUBLICATIONS

  • Thrombospondin-2 facilitates assembly of a type-I collagen-rich matrix in marrow stromal cells undergoing osteoblastic differentiation.
  • Two molecular weight species of thrombospondin-2 are present in bone and differentially modulated in fractured and nonfractured tibiae in a murine model of bone healing.
  • Two Molecular Weight Species of Thrombospondin-2 Are Present in Bone and Differentially Modulated in Fractured and Nonfractured Tibiae in a Murine Model of Bone Healing
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    20 TRIPLES      17 PREDICATES      21 URIs      9 LITERALS

    Subject Predicate Object
    1 grants:8761e04d109403ad77062dddc426c588 sg:abstract DESCRIPTION (provided by applicant): The objective of the 5 year career development plan outlined in this KO1 application is to foster the development of the candidate, Dr. Alford into a productive, independent investigator in the field of osteoblast cellular and extracellular matrix biology. Under the guidance of her mentors, Drs Steven A Goldstein and Renny T Franceschi, and through regular interactions with expert consultants, Stephen J. Weiss and Kurt D. Hankenson, the candidate will carry out the proposed research as a member of the Orthopaedic Research Laboratories in the Department of Orthopaedic Surgery at the University of Michigan. In the 5 year research plan proposed here, we will utilize primary MSC harvested from TSP2-null mice and their littermates in a well established in vitro model of osteoblastogenesis to test the global hypothesis that matrix-bound TSP2 makes specific contributions to osteoblast lineage progression which are dependent on the differentiation state of the cell, as well as on the unique extracellular milieu associated with matrix assembly, maturation and mineralization. Specifically, in aim 1 we will address the working hypothesis that in the context of early osteoblast-differentiation events, TSP2 promotes the assembly of a type I collagen-rich osteoblast-derived extracellular matrix, and as a result, it indirectly promotes collagen-dependent signal transduction events that are critical for osteoblast differentiation. In specific aim 2, we will address the premise that, in the context of matrix mineralization, TSP2 makes an additional unique contribution to osteoblast maturation. Specifically, we hypothesize that TSP2 is proteolytically processed to release biologically relevant fragments that affect matrix mineralization. Together, the experiments outlined in this proposal will define differentiation-stage dependent contributions that TSP2 makes to osteoblast lineage progression and matrix mineralization.
    2 sg:endYear 2016
    3 sg:fundingAmount 561655.0
    4 sg:fundingCurrency USD
    5 sg:hasContribution contributions:d8fa8e96377c6ecda91ca60d1ab45d8f
    6 sg:hasFieldOfResearchCode anzsrc-for:06
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    8 sg:hasFundedPublication articles:7c0c4752d3c7c485eeca5b8f9f53fc3c
    9 articles:ed777d011c00095d6b0303b2dedd043c
    10 articles:ff4c9a3f2d240a8f85413c6b56d9b6f0
    11 sg:hasFundingOrganization grid-institutes:grid.420086.8
    12 sg:hasRecipientOrganization grid-institutes:grid.214458.e
    13 sg:language English
    14 sg:license http://scigraph.springernature.com/explorer/license/
    15 sg:scigraphId 8761e04d109403ad77062dddc426c588
    16 sg:startYear 2011
    17 sg:title Functional Characterization of Thrombospondin-2 in Bone Extracellular Matrix
    18 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=8895837
    19 rdf:type sg:Grant
    20 rdfs:label Grant: Functional Characterization of Thrombospondin-2 in Bone Extracellular Matrix
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