The skin is the largest organ of the human body and serves as a barrier against the environment. One of the most common environmental insults to the skin is ultraviolet radiation (UVR), a ubiquitous carcinogen. Cutaneous UVB exposure initiates the pigmentation cascade, with the upregulation of pro- opiomelanocortin (POMC) in epidermal keratinocytes. POMC is post-translationally cleaved to yield melanocortin peptides essential for stimulating production of protective melanin. Interestingly, cleavage of POMC also yields the endogenous opioid, ?-endorphin (?-end), leading to a systemic increase in plasma levels of ?-end that is sufficient to cause `tanning addiction' in mice. ?-end is an endogenous opioid that binds to the -opioid receptor (-OPR) expressed in the central and peripheral nervous systems (CNS, PNS). Though the analgesic effects of opioids are well established, a role in suppressing inflammation has been demonstrated in animal models. Our observation that loss of ?-end or -OPR in mice results in a severe cutaneous inflammatory response to UVB suggests that opioids suppress inflammation in the skin. We hypothesize that UVR-induced ?-end may have acute beneficial effects. This proposal will elucidate the contribution of both the local, cutaneous effects, and the global, systemic, effects of opioid signaling on cutaneous inflammation.
Aim 1 will establish the experimental `sunburn' conditions to study the role of opioids in cutaneous inflammation using mice with and without functioning opioid signaling. In addition to studying the role of ?-end after UVR, we will determine if ?-end suppresses cutaneous inflammation in models of cutaneous inflammatory conditions, such as atopic dermatitis and psoriasis. Lastly, using histopathological analysis and flow cytometry techniques, we will characterize the local inflammatory response in ?-end KO, -OPR KO, and C57BL6 mice to identify contributing factors to the cutaneous phenotype.
In Aim 2 we will explore the mechanism by which ?-end exerts its anti-inflammatory effects. We hypothesize that keratinocyte-derived ?-endorphin acts on immune cells and peripheral nerve fibers to suppress inflammation. Using the murine model, we will immunophenotype opioid-deficient mice and control mice to determine differential numbers of immune cells in baseline and UV-exposed conditions. Next, using bone marrow transplantation, we will determine if expression of -OPR on immune cells is sufficient to affect the cutaneous inflammatory response to UVR. Lastly, to distinguish between potential contributions of the CNS and PNS to the anti-inflammatory effects of opioids, we will exploit pharmacological manipulation of the opioid signaling pathway. Combined, these studies may reveal a clinically relevant application and mechanism of topically-applied, peripherally-acting opioids as anti-inflammatory treatments for several cutaneous inflammatory conditions.
Every year, over 35 million Americans will experience inflammatory skin conditions, including acute conditions such as sunburn and chronic conditions such as psoriasis. Unfortunately, current treatment options are limited due to negative side effects on the skin, such as thinning of the skin or increased susceptibility to infection. We will explore the anti-inflammatory effects of opioids in the skin and the potential use of topically applied opioids for inflammatory skin conditions.
|Kim, Min Hye; Choi, Seng Jin; Choi, Hyun Il et al. (2018) Lactobacillus plantarum-derived Extracellular Vesicles Protect Atopic Dermatitis Induced by Staphylococcus aureus-derived Extracellular Vesicles. Allergy Asthma Immunol Res 10:516-532|
|Scherer, Michael; Canham, Sarah; Voas, Robert B et al. (2018) Intercorrelation of Alcohol and Other Drug Use Disorders among a National Sample of Drivers. J Psychoactive Drugs 50:143-150|
|Leem, Jungtae; Lee, Seunghoon; Park, Yeoncheol et al. (2017) Effectiveness and safety of moxibustion treatment for non-specific lower back pain: protocol for a systematic review. BMJ Open 7:e014936|
|Kim, Min Hye; Rho, Mina; Choi, Jun Pyo et al. (2017) A Metagenomic Analysis Provides a Culture-Independent Pathogen Detection for Atopic Dermatitis. Allergy Asthma Immunol Res 9:453-461|
|Neychev, Vladimir; Steinberg, Seth M; Cottle-Delisle, Candice et al. (2015) Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical tria BMJ Open 5:e008248|
|De, Debojyoti; Jeong, Myong-Ho; Leem, Young-Eun et al. (2014) Inhibition of master transcription factors in pluripotent cells induces early stage differentiation. Proc Natl Acad Sci U S A 111:1778-83|
|Torres, Pedro; Romano, Eduardo; Voas, Robert B et al. (2014) The relative risk of involvement in fatal crashes as a function of race/ethnicity and blood alcohol concentration. J Safety Res 48:95-101|
|Kelley-Baker, Tara; Lacey, John H; Voas, Robert B et al. (2013) Drinking and driving in the United States: comparing results from the 2007 and 1996 National Roadside Surveys. Traffic Inj Prev 14:117-26|
|Voas, Robert B; Lacey, John H; Jones, Kristina et al. (2013) Drinking drivers and drug use on weekend nights in the United States. Drug Alcohol Depend 130:215-21|
|Voas, Robert B; Torres, Pedro; Romano, Eduardo et al. (2012) Alcohol-related risk of driver fatalities: an update using 2007 data. J Stud Alcohol Drugs 73:341-50|
Showing the most recent 10 out of 27 publications