The overall goal of our research is to preserve the integrity of the extracellular matrix of the corneal epithelial basement membrane zone after mustard injury, thereby providing the epithelial cells a substratum on which to recover. Many studies on mustards have focused on their direct impact on epithelial cells. While these cells have ultimate control, their extracellular matrix is a key factor in their survival, and serves an instructive function, facilitating their migration, proliferation, or differentiation and this represents the focus of our studies. Severely altered matrices, which occur as a result of sulfur mustard exposure, appear to lack the appropriate cues, thereby preventing cells from remodeling the tissue back to a normal state. To overcome this, our approach to developing ocular countermeasures is to identify agents that inhibit basement membrane degrading matrix metalloproteinases, in particular, ADAM17/TACE, which cleaves a component of the adhesion complex between the epithelial and stromal cell layers;we are also investigating the role of autophagy in removing cross-linked proteins in vesicant-modified basement membrane. During the next grant period, we will also continue studies working with the Pharmacology and Drug Development Core and the Medicinal Chemistry and Pharmaceutics Core to further develop doxycydine-loaded hydrogels as potential sulfur mustard and nitrogen mustard countermeasures in the cornea. Our preliminary data and published papers demonstrate that these hydrogels are remarkably effective in mitigating sulfur mustard-induced corneal injury;additional studies are needed to improve their efficacy in the rabbit eye model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54AR055073-06
Application #
8210200
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (54))
Project Start
Project End
Budget Start
2011-09-09
Budget End
2012-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$588,285
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Francis, Mary; Sun, Richard; Cervelli, Jessica A et al. (2017) Editor's Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury. Toxicol Sci 155:182-195
Chmielowski, Rebecca A; Abdelhamid, Dalia S; Faig, Jonathan J et al. (2017) Athero-inflammatory nanotherapeutics: Ferulic acid-based poly(anhydride-ester) nanoparticles attenuate foam cell formation by regulating macrophage lipogenesis and reactive oxygen species generation. Acta Biomater 57:85-94
Venosa, Alessandro; Gow, James G; Hall, LeRoy et al. (2017) Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor. Toxicol Sci 157:222-234
Yang, Shaojun; Jan, Yi-Hua; Mishin, Vladimir et al. (2017) Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells. Chem Res Toxicol 30:1406-1418
Faig, Jonathan J; Moretti, Alysha; Joseph, Laurie B et al. (2017) Biodegradable Kojic Acid-Based Polymers: Controlled Delivery of Bioactives for Melanogenesis Inhibition. Biomacromolecules 18:363-373
Sunil, Vasanthi R; Vayas, Kinal N; Fang, Mingzhu et al. (2017) World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung. Exp Mol Pathol 102:50-58
Malaviya, Rama; Laskin, Jeffrey D; Laskin, Debra L (2017) Anti-TNF? therapy in inflammatory lung diseases. Pharmacol Ther 180:90-98
Joseph, Laurie B; Composto, Gabriella M; Perez, Roberto M et al. (2017) Sulfur mustard induced mast cell degranulation in mouse skin is inhibited by a novel anti-inflammatory and anticholinergic bifunctional prodrug. Toxicol Lett :
Francis, Mary; Groves, Angela M; Sun, Richard et al. (2017) Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure. Toxicol Sci 155:474-484
Lasfar, Ahmed; de laTorre, Andrew; Abushahba, Walid et al. (2016) Concerted action of IFN-? and IFN-? induces local NK cell immunity and halts cancer growth. Oncotarget 7:49259-49267

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