Utilization of Collagen Remodeling Pathways to Control Gene Delivery

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1159466/ SullivanIntellectual Merit: The overall objective of the proposed project is to develop DNA-linked collagen hydrogels whose remodeling by fibroblast cells will stimulate DNA release and efficient gene delivery. Ultimately, these novel scaffolds will be used to trigger robust (and low cost) in situ expression of growth factors (GFs) to enable healing of chronic wounds and other damaged tissues. In the proposed approach, collagen scaffolds will be modified with plasmid DNAs by newly linking DNA-binding peptides (DBPs) and collagen mimetic peptides (CMPs) with previously established capacities for gene transfer (DBPs) and collagen modification (CMPs). The proposed work will test the following hypotheses: (1) native collagen remodeling processes involving collagen degradation [by matrix metalloproteinases (MMPs)] and collagen endocytosis [by alpha2 beta1 integrins and caveolin-1] will trigger the release and endocytosis of collagen-linked DNA "polyplexes"; (2) collagen linkage will initiate DNA trafficking through efficient gene delivery routes involving caveolin-1. Completion of the proposed aims should provide fundamentally new strategies to understand and direct gene delivery, and in the long term, will foster new materials and therapeutic strategies in tissue repair.Broader Impacts: Given the wealth of target GFs and the widespread use of collagen-based materials, the proposed studies will advance the use of collagen-mediated gene delivery not only in chronic wound repair, but also in multiple other applications such as implant functionalization and regenerative medicine. The proposed efforts are also designed to provide new research and career development opportunities, including industrial mentorship, for undergraduates, high school interns, and underrepresented groups, by building on existing undergraduate research and outreach infrastructure at UD, as well as on previous educational activities of Kiick and Sullivan.