instmctions): (Project 2, Maytin) Hyaluronan as a Regulator of Cutaneous Inflammation and Fibrosis - Delayed and abnormal wound healing is a serious health problem for millions of patients suffering each year from non- healing skin ulcers, or from excessive scarring after trauma. This project proposes to develop a better understanding of the role of hyaluronan (HA) during cutaneous wound repair. HA is an important component of the pericellular coat (glycocalyx) of fibroblasts and endothelial cells (ECs) in skin. Interestingly, HA is most abundant in a newly-recognized zone at the junction between the dermal and adipose layers, where neutrophils (PMNs) and myofibroblasts (MFs) appear early during wound healing. Until now, few wound healing models were available to study roles of HA during wound repair. We propose to use a new knockout mouse model, Has1/Has3 double-null mice, that show a dramatic phenotype during wound healing. These mice have: 1) accelerated wound closure;2) enhanced PMN recruitment into the woundbed, 3) accelerated myofibroblast differentiation in the healing scar. Our central hypothesis is that HA has critical roles In PMN recruitment and In TGFp-mediated differentiation of myofibroblasts (MFs). Our goal Is to elucidate the underlying mechanisms.
Aim 1 will determine how the HA glycocalyx on ECs regulates PMN recruitment at postcapillary venules after wounding, through experiments in vivo (Intravital microscopy of PMNs in venules) and in cultured cells. The in vitro experiments will examine adhesion and transmigration of PMNs in monolayers of primary murine microvascular endothelial cells from Has1/Has3 mice and wildtype (WT) controls.
Aim 2 will determine mechanisms by which the HA glycocalyx regulates MF differentiation, via interactions between the HA receptor CD44 and TGF3 receptor-mediated pathways. Fibroblasts will be evaluated in collagen gel contraction assays for rates of MF conversion in response to TGFp. Finally, we will test the hypothesis that excessive inflammation and MF differentiation may be undesirable and may result in poorer quality of repair, by performing tensiometric measurements of scar breaking strength. The project collaborates extensively with other Research Team members, and takes full advantage of Core B.
The anticipated benefits of the proposed work for public health will be a new body of knowledge about HA and its place in the glycobiology in wound healing, new information that could ultimately suggest new approaches and potential targets for therapeutic intervention.
|Kim, Yeojung; West, Gail A; Ray, Greeshma et al. (2017) Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Matrix Biol :|
|Kessler, Sean P; Obery, Dana R; Nickerson, Kourtney P et al. (2017) Multifunctional Role of 35 Kilodalton Hyaluronan in Promoting Defense of the Intestinal Epithelium. J Histochem Cytochem :22155417746775|
|Saikia, Paramananda; Bellos, Damien; McMullen, Megan R et al. (2017) MicroRNA 181b-3p and its target importin ?5 regulate toll-like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol. Hepatology 66:602-615|
|Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Emond, Audrey et al. (2017) The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity. Elife 6:|
|Ghatak, Shibnath; Markwald, Roger R; Hascall, Vincent C et al. (2017) Transforming growth factor ?1 (TGF?1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts. J Biol Chem 292:10465-10489|
|Petrey, Aaron C; de la Motte, Carol A (2017) The extracellular matrix in IBD: a dynamic mediator of inflammation. Curr Opin Gastroenterol 33:234-238|
|Ghatak, Shibnath; Hascall, Vincent C; Markwald, Roger R et al. (2017) Transforming growth factor ?1 (TGF?1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem 292:10490-10519|
|Asano, Keiichi; Nelson, Courtney M; Nandadasa, Sumeda et al. (2017) Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis. Sci Rep 7:17225|
|Hendee, Kathryn; Wang, Lauren Weiping; Reis, Linda M et al. (2017) Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree. Hum Mutat 38:1485-1490|
|Stober, Vandy P; Johnson, Collin G; Majors, Alana et al. (2017) TNF-stimulated gene 6 promotes formation of hyaluronan-inter-?-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. J Biol Chem 292:20845-20858|
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