The long term goal of this research project is to enhance our understanding of wound healing. Multidisciplinary, in vitro and in vivo studies will describe cell-matrix interactions and their function in the regulation of cutaneous repair. Research will focus on the mechanisms of re-epithelization and fibroplasia. During the next 5 years we aim to answer the following questions: 1. Is activation of epidermal adhesion regulated by basement membrane and growth factors? We will analyze changes that occur in the expression of specific integrin adhesion receptors during activation of epidermal adhesion and migration. We will determine if basement membrane and transforming growth factor beta (TGF-BETA) regulate activation of epidermal cell adhesion. 2. What are the effects of cell adhesion proteins and growth factors on contraction-mediated regulation of connective tissue biogenesis? We will use long term, ascorbate-supplemented, fibroblast cultures as an in vitro model of new connective tissue biogenesis. We will study the regulation of tissue biogenesis by extracellular matrix contraction under the influence of adhesion proteins (fibronectin and vitronectin) and platelet released factors (TGF-BETA and PDGF). 3.How does the release of contracted collagen gels from tension regulate cell growth and biosynthetic activity? Collagen gels contracted by fibroblasts will be released from tension by mechanical manipulation. Subsequent changes in cell morphology and biosynthetic activity will be measured. 4. Do arg-gly-glu (RGE)-containing collagen peptides inhibit wound contraction? RGE-containing peptides that correspond to collagen type I sequences will be tested for their ability to inhibit collagen gel contraction in vitro. The most active peptide will be tested to learn if it inhibits full thickness wound contraction in vivo. 5. What is the distribution and activity of adhesion proteins in wound fluid? We will use several types of wound fluid: suction blister, chronic skin ulcer, burn, and surgical (mastectomy). The distribution of adhesion proteins in the various wound fluids and proteolysis of fibronectin in the wounds will be analyzed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Texas Sw Medical Center Dallas
Schools of Medicine
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da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick (2015) PDGF?stimulated dispersal of cell clusters and disruption of fibronectin matrix on three-dimensional collagen matrices requires matrix metalloproteinase-2. Mol Biol Cell 26:1098-105
Liu, Zhenan; Ho, Chin-Han; Grinnell, Frederick (2014) The different roles of myosin IIA and myosin IIB in contraction of 3D collagen matrices by human fibroblasts. Exp Cell Res 326:295-306
Velasquez, Lissette S; Sutherland, Lillian B; Liu, Zhenan et al. (2013) Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc Natl Acad Sci U S A 110:16850-5
da Rocha-Azevedo, Bruno; Grinnell, Frederick (2013) Fibroblast morphogenesis on 3D collagen matrices: the balance between cell clustering and cell migration. Exp Cell Res 319:2440-6
Grinnell, Frederick; Ho, Chin-Han (2013) The effect of growth factor environment on fibroblast morphological response to substrate stiffness. Biomaterials 34:965-74
da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick (2013) Fibroblast cluster formation on 3D collagen matrices requires cell contraction dependent fibronectin matrix organization. Exp Cell Res 319:546-55
Rhee, Sangmyung; Ho, Chin-Han; Grinnell, Frederick (2010) Promigratory and procontractile growth factor environments differentially regulate cell morphogenesis. Exp Cell Res 316:232-44
Grinnell, Frederick; Petroll, W Matthew (2010) Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol 26:335-61
Miron-Mendoza, Miguel; Seemann, Joachim; Grinnell, Frederick (2010) The differential regulation of cell motile activity through matrix stiffness and porosity in three dimensional collagen matrices. Biomaterials 31:6425-35
Jiang, Hongmei; Rhee, Sangmyung; Ho, Chin-Han et al. (2008) Distinguishing fibroblast promigratory and procontractile growth factor environments in 3-D collagen matrices. FASEB J 22:2151-60

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