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 #
7U54AR055073-08
Application #
8545530
Study Section
Special Emphasis Panel (ZRG1-MDCN-J)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$310,859
Indirect Cost
Name
Rbhs-Robert Wood Johnson Medical School
Department
Type
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Malaviya, Rama; Laskin, Jeffrey D; Laskin, Debra L (2014) Oxidative stress-induced autophagy: role in pulmonary toxicity. Toxicol Appl Pharmacol 275:145-51
Joseph, Laurie B; Heck, Diane E; Cervelli, Jessica A et al. (2014) Structural changes in hair follicles and sebaceous glands of hairless mice following exposure to sulfur mustard. Exp Mol Pathol 96:316-27
Massa, Christopher B; Scott, Pamela; Abramova, Elena et al. (2014) Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction. Toxicol Appl Pharmacol 278:53-64
Mishin, Vladimir; Heck, Diane E; Laskin, Debra L et al. (2014) Human recombinant cytochrome P450 enzymes display distinct hydrogen peroxide generating activities during substrate independent NADPH oxidase reactions. Toxicol Sci 141:344-52
Zheng, Ruijin; Heck, Diane E; Black, Adrienne T et al. (2014) Regulation of keratinocyte expression of stress proteins and antioxidants by the electrophilic nitrofatty acids 9- and 10-nitrooleic acid. Free Radic Biol Med 67:1-9
Pinkerton, Nathalie M; Zhang, Stacey W; Youngblood, Richard L et al. (2014) Gelation chemistries for the encapsulation of nanoparticles in composite gel microparticles for lung imaging and drug delivery. Biomacromolecules 15:252-61
Jan, Yi-Hua; Heck, Diane E; Dragomir, Ana-Cristina et al. (2014) Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol 27:882-94
Page, Eric J; Gray, Joshua P (2014) Agents of Bioterrorism: Curriculum and Pedagogy in an Online Masters Course. J Toxicol Educ 1:31-53
Chang, Yoke-Chen; Wang, James D; Hahn, Rita A et al. (2014) Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard. Toxicol Appl Pharmacol 280:236-44
Chen, Peiming; Zhang, Xiaoping; Jia, Lee et al. (2014) Optimal structural design of mannosylated nanocarriers for macrophage targeting. J Control Release 194:341-9

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