Tissue injury initiates a series of temporally- and spatially-integrated events requiring interactions between cells and proteins in the surrounding extracellular matrix (ECM). Many factors can delay wound healing, including infection, advanced age, diabetes, and renal disease. Disruptions in the healing process can lead to non-healing, chronic wounds or conversely, result in the development of fibrotic scars that compromise organ function. The ECM of wounds is composed of collagens, glycoproteins, and proteoglycans. These proteins provide an array of cell adhesion sites, cell migration pathways, and proliferation signals to cells, and impart mechanical stability to the healing wound. Fibronectin (FN) is a principal component of the ECM. Soluble FN molecules are assembled into the ECM as insoluble, fibrillar strands via a cell-dependent process. In turn, the interaction of cells with the ECM form of FN stimulates cell functions critical for tissue repair. FN matrix assembly also promotes collagen matrix deposition and increases tissue tensile strength. FN matrix assembly is normally rapidly up- regulated following tissue injury, while reduced FN matrix deposition is associated with chronic wounds. Hence, therapeutic approaches that circumvent diminished FN matrix assembly by providing injured cells with synthetic ECM-like FNs may accelerate wound healing. In this project, we will determine the role of FN matrix polymerization in normal wound repair and understand how this process may be altered in chronic wounds. Additionally, we will develop recombinant FN matrix mimetics as accelerators of tissue regeneration and ask whether these engineered proteins promote tissue repair in a mouse model of impaired wound healing. This novel therapeutic approach should eliminate the need for cell-dependent FN ECM assembly in the chronic wound and thus, promote wound repair by providing injured tissues with key ECM FN-specific signals and structural information. New treatment approaches are needed to rapidly close burns and chronic wounds to decrease the risk of infection, prevent fluid loss, and promote the natural healing process. We envision the clinical use of these mimetics as a means to rapidly up-regulate cell function and tissue mechanics in chronic, non-healing wounds.

Public Health Relevance

Many factors can delay wound healing, including infection, advanced age, diabetes, and renal disease. New treatment approaches are needed to rapidly close burns and chronic wounds to decrease the risk of infection, prevent fluid loss, and promote the natural healing process. Here, we will develop the use of recombinant extracellular matrix analogs as a novel therapy to rapidly up-regulate cell function and tissue mechanics in chronic, non-healing wounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081513-04
Application #
8225193
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Somers, Scott D
Project Start
2009-04-05
Project End
2013-06-30
Budget Start
2012-02-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$310,423
Indirect Cost
$109,502
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Roy, Daniel C; Hocking, Denise C (2013) Recombinant fibronectin matrix mimetics specify integrin adhesion and extracellular matrix assembly. Tissue Eng Part A 19:558-70
Sevilla, Carlos A; Dalecki, Diane; Hocking, Denise C (2013) Regional fibronectin and collagen fibril co-assembly directs cell proliferation and microtissue morphology. PLoS One 8:e77316
Roy, Daniel C; Mooney, Nancie A; Raeman, Carol H et al. (2013) Fibronectin matrix mimetics promote full-thickness wound repair in diabetic mice. Tissue Eng Part A 19:2517-26
Lefort, Craig T; Wojciechowski, Katherine; Hocking, Denise C (2011) N-cadherin cell-cell adhesion complexes are regulated by fibronectin matrix assembly. J Biol Chem 286:3149-60
Roy, Daniel C; Wilke-Mounts, Susan J; Hocking, Denise C (2011) Chimeric fibronectin matrix mimetic as a functional growth- and migration-promoting adhesive substrate. Biomaterials 32:2077-87