In this project. Dr. Donald Gerecke will lead an effort to elucidate basic mechanisms of vesicant damage in the skin with the ultimate goal of identifying new targets in the tissue for therapeutic intervention and drug development. Vesicants are known to alkylate and crosslink molecules disrupting their biological activity. This can cause damage to the structure and function of tissues. The specific pathogenic and molecular mechanisms responsible for vesicant-induced skin injury remain unclear, but modifications of both intracellular and extracellular resident proteins are considered to be key factors. His laboratory group has discovered that this process can activate the endoplasmic reticulum stress pathways in keratinocytes.
His specific aims are to examine the contribution of the endoplasmic reticulum stress response to vesicant injury and evaluate medical countermeasures specifically targeting this pathway. He will determine if vesicants alter the binding of laminin-332, a critical matrix protein which anchors basal keratinocytes to the basement membrane, to its natural structural partners causing detachment of the basal keratinocytes from the underlying dermis, a process that can result in blistering. He will also assess whether alkylation of laminin-332 affects the migration properties of keratinocytes, a process key for wound repair. Finally, plans are to work with the Pharmacology and Drug Development Core and the Medicinal Chemistry and Pharmaceutics Core to further evaluate compounds identified as potential sulfur mustard countermeasures in the skin. He will also continue research and development efforts with unique doxycydine-loaded hydrogels that our Center has shown to be effective against nitrogen mustard-induced skin injury in several different animal models.
|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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