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.
|Hope, Chelsea; Foulcer, Simon; Jagodinsky, Justin et al. (2016) Immunoregulatory roles of versican proteolysis in the myeloma microenvironment. Blood 128:680-5|
|Benz, Brian A; Nandadasa, Sumeda; Takeuchi, Megumi et al. (2016) Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion. Dev Biol 416:111-22|
|Dong, Yifei; Arif, Arif; Olsson, Mia et al. (2016) Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-Î±, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages. Sci Rep 6:36928|
|Abbadi, Amina; Lauer, Mark; Swaidani, Shadi et al. (2016) Hyaluronan Rafts on Airway Epithelial Cells. J Biol Chem 291:1448-55|
|Apte, Suneel S (2016) Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis. Biochem J 473:e1-4|
|Petrey, Aaron C; Obery, Dana R; Kessler, Sean P et al. (2016) Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis. Am J Pathol 186:2390-403|
|Janssen, Lauriane; Dupont, Laura; Bekhouche, Mourad et al. (2016) ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis. Angiogenesis 19:53-65|
|Soroosh, Artin; Albeiroti, Sami; West, Gail A et al. (2016) Crohn's Disease Fibroblasts Overproduce the Novel Protein KIAA1199 to Create Proinflammatory Hyaluronan Fragments. Cell Mol Gastroenterol Hepatol 2:358-368.e4|
|Matuska, Brittany; Comhair, Suzy; Farver, Carol et al. (2016) Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions. Am J Respir Cell Mol Biol 55:576-585|
|Petrey, Aaron C; de la Motte, Carol A (2016) Thrombin Cleavage of Inter-Î±-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix. J Biol Chem 291:24324-24334|
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