Molecular Determinants of Intergrin-dependent Mechanotransduction

Boston Children'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Cellular mechanotransduction - the mechanism by which cells sense mechanical forces and convert them into changes in cellular biochemistry - is critical for control of development of both large and small blood vessels. Deregulation of this process may contribute to the development of various angiogenesis-dependent diseases. Force transduction from the extracellular matrix (ECM) to the cell occurs mainly through transmembrane receptors called integrins. Many signaling cascades are activated by integrins in a force- dependent manner but the initial mechanism of mechanochemical signal conversion is unclear. Recent data from Dr. Ingber's laboratory shows that large, heterotrimeric G proteins are involved in integrin-dependent responses to force and may bind directly to the integrin. Based on these data I propose to determine the molecular mechanism of G protein recruitment to and activation by integrins. I will probe integrin mutants using magnetic micromanipulation, biochemistry and confocal microscopy to determine which domains of integrin are required for integrin-dependent response to force. These studies will improve our understanding of mechanotransduction and could suggest novel anti-angiogenic drug targets.