Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY This application proposes a customized research training plan designed to promote the development of the applicant into an independent investigator. The plan includes advanced training in both bioinformatics and laboratory experimentation, along with tailored professional and career development opportunities. The training plan is supported by the outstanding availability of local and institutional resources at UIC. The proposed research will examine the mechanisms that control scar formation, a common result of the healing response. In adults, the outcome of wound repair is almost always a fibrous scar composed of disorganized extracellular matrix (ECM). Although regulation of scar formation is complex, a key feature is fibroblast (FB) activation, which generates ECM and contractile forces. Scarring and fibrosis occurs in many tissues and can cause significant impairments of the organ system affected. Recent studies in our lab have identified a novel FB function in wounds that may be linked to scar formation. These studies show that wound FBs can act as non- professional phagocytes and ingest apoptotic cells. Following apoptotic cell engulfment, FBs develop a fibrotic phenotype with enhanced migration, increased contractility (a-SMA expression), and increased collagen synthesis. One factor found to be significantly upregulated in fibrotic phagocytic FBs is microfibril-associated protein 5 (MFAP5 or microfibril-associated glycoprotein 2/MAGP2). MFAP5 influences microfibril function and can regulate cell signaling pathways. Interestingly, MFAP5 has been linked to fibrosis in several human diseases, including some cancers and fibrotic diseases. Still, little is known regarding its role in wound healing and scar formation. Therefore, the goal of this study is to gain a better understanding of the function of MFAP5 in skin healing and scar formation. We hypothesize that upregulation of MFAP5 in the healing skin wound modifies the FB response and promotes scar formation. In this study, the role of MFAP5 in wound healing will be investigated in Mfap5-/- mice, a well-established Mfap5 knock out mouse line. The effect of MFAP5 on FB phenotype will be further investigated in vitro. This proposal will utilize in vivo and in vitro wound healing assays and advanced bioinformatics techniques. Aim 1 will assess how the loss of MFAP5 affects wound healing, including scar collagen content and architecture, wound breaking strength, myofibroblast activation, angiogenesis, and wound closure. Single-cell RNA sequencing will be used to identify the FB subpopulation that produces MFAP5 during wound healing. Aim 2 will examine how MFAP5 influences FB function and gene expression by utilizing in vitro wound healing assays as well as bulk RNA-sequencing and functional pathway analysis. Together, the Aims will lead to a better understanding of the importance of MFAP5 in healing skin wounds and scar formation. Information gained from the proposed research may lead to the development of novel therapeutics and/or discovery of a prognostic biomarker for treatment of fibrotic diseases.
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