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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107147-04
Application #
8669086
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$363,328
Indirect Cost
$131,523
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Alkhouri, N; Eng, K; Cikach, F et al. (2015) Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls. Pediatr Obes 10:23-9
Dababneh, Luma; Cikach, Frank; Alkukhun, Laith et al. (2014) Sublingual microcirculation in pulmonary arterial hypertension. Ann Am Thorac Soc 11:504-12
Foulcer, Simon J; Nelson, Courtney M; Quintero, Maritza V et al. (2014) Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5. J Biol Chem 289:27859-73
Dubail, Johanne; Aramaki-Hattori, Noriko; Bader, Hannah L et al. (2014) A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis 52:702-12
Aytekin, Metin; Tonelli, Adriano R; Farver, Carol F et al. (2014) Leptin deficiency recapitulates the histological features of pulmonary arterial hypertension in mice. Int J Clin Exp Pathol 7:1935-46
Coulson-Thomas, Vivien Jane; Gesteira, Tarsis Ferreira; Hascall, Vincent et al. (2014) Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx. J Biol Chem 289:23465-81
Ghatak, Shibnath; Bogatkevich, Galina S; Atnelishvili, Ilia et al. (2014) Overexpression of c-Met and CD44v6 receptors contributes to autocrine TGF-?1 signaling in interstitial lung disease. J Biol Chem 289:7856-72
Navaneethan, Sankar D; Wehbe, Edgard; Heresi, Gustavo A et al. (2014) Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 9:855-63
Xu, Weiling; Janocha, Allison J; Leahy, Rachel A et al. (2014) A novel method for pulmonary research: assessment of bioenergetic function at the air-liquid interface. Redox Biol 2:513-9
Ghatak, Shibnath; Misra, Suniti; Norris, Russell A et al. (2014) Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis. J Biol Chem 289:8545-61

Showing the most recent 10 out of 36 publications