Intellectual Merit. The research objective is to elucidate the fundamental structural and molecular mechanisms involved in formation of the ternary complex of the matricellular protein thrombospondin-1 (TSP1), the cell surface protein calreticulin (CRT), and LDL receptor-related protein 1 (LRP1) which is induced by TSP1 binding to cell surface CRT and which signals intermediate adhesion, cell migration, anoikis resistance, and collagen production. Wound healing in response to injury requires well-coordinated integration of the complex biological and molecular events associated with cell adhesion, cell migration, and extracellular matrix remodeling. Binding of TSP1 to cell surface CRT promotes binding of CRT to LRP1 to form the TSP1-CRT-LRP1 ternary complex, which is important for cellular events critical for wound healing and tissue repair. Although the importance of TSP1 and CRT interactions for cell functions related to tissue repair and remodeling are clear, the specific structural and molecular mechanism by which TSP1 engagement of CRT initiates signaling complex formation with LRP1 remains unclear. The PI will use the integration of computational modeling and biochemical and biological experimental approaches to implement the research objective.
Broader Impact. The educational objective is to educate and retain graduate, undergraduate, high and middle school students, broadening the participation of minority and female students in science and engineering in a sustainable fashion, and to integrate the education, outreach and knowledge dissemination with the research activities. Successful completion of the proposed project will have a transformative impact on research, educational, and outreach activities. Research discoveries regarding structural and molecular mechanisms of the role of the TSP1-CRT interactions in regulation of CRT-induced TSP1-CRT-LRP1 ternary complex formation and subsequent regulation of intermediate adhesion and collagen expression and deposition could lead to the identification of novel strategies and drug targets for modifying aberrant tissue repair responses that occur in scarring or the foreign body response or conversely in wound healing deficiencies. The educational efforts will recruit and sustain talented and diverse students at multiple levels (graduate, undergraduate, high and middle school) who are excited about science and engineering and who possess a desire to succeed, will help to promote diversity in the science and engineering workforce, and will promote the knowledge dissemination.
