Mammalian epidermis is poised at the interface with the environment, and it must both prevent excess transcutaneous water loss in a desiccating terrestrial environment, and protect underlying tissues from toxic mechanical and chemical insults. In addition to blocking the penetration of xenobiotics and chemical toxins, it mitigates the adverse effects of ultraviolet radiation and other form of oxidative stress (OS). Ceramide (Cer), as members of the nitrogen-containing lipid class (sphingolipids), represent one of the primary lipid constituents of the outermost layer of the epidermis, the stratum corneum, in which this critical permeability/xenobiotic/ antioxidant barrier resides. In addition to their critical role as bulk membrane constituents in barrier function, various Cer metabolites also have emerged as critical for numerous other cellular functions. Pertinently, OS from a variety of stressors increases cellular Cer levels, thereby triggering increased (potentially premature) apoptosis, and excessive apoptosis or premature differentiation can impact epidermal function negatively. It is our hypothesis that epidermal keratinocytes deploy two classes of protective mechanisms that restrict levels of intracellular Cer, both from the ever-present risk of exposure to oxidative stressors, and from the high levels of Cer production required to meet barrier requirements during epidermal differentiation: 1) distal metabolism/catabolism of excess Cer to non-apoptotic metabolites;and 2) rapid sequestration/externalization of Cer, as glucosylceramide and sphingomyelin precursors, within the epidermal lamellar body secretory system. In our first aim, we will delineate the mechanisms that protect keratinocytes from Cer generated in response to oxidative stress. In our second aim, we will determine the mechanisms that protect the epidermis from upregulated Cer production for maintenance of the permeability barrier. Because epidermis is inherently at higher potential risk than other tissues, due to its exposure to external oxidative stressors, and because it generates abundant amounts of Cer for the epidermal barrier, it is important to understand those mechanism(s) that regulate intracellular Cer levels, thereby protecting epidermis from premature Cer-induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051077-05
Application #
7565977
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Baker, Carl
Project Start
2005-01-01
Project End
2011-11-30
Budget Start
2008-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$289,960
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Park, Kyungho; Ikushiro, Hiroko; Seo, Ho Seong et al. (2016) ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex. Proc Natl Acad Sci U S A 113:E1334-42
Kim, Young-Il; Park, Kyungho; Kim, Jong Youl et al. (2014) An endoplasmic reticulum stress-initiated sphingolipid metabolite, ceramide-1-phosphate, regulates epithelial innate immunity by stimulating ?-defensin production. Mol Cell Biol 34:4368-78
Uchida, Yoshikazu (2014) Ceramide signaling in mammalian epidermis. Biochim Biophys Acta 1841:453-62
Park, Kyungho; Kim, Young-Il; Shin, Kyong-Oh et al. (2014) The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism. J Nutr Biochem 25:734-40
Park, Kyungho; Elias, Peter M; Hupe, Melanie et al. (2013) Resveratrol stimulates sphingosine-1-phosphate signaling of cathelicidin production. J Invest Dermatol 133:1942-9
Loiseau, Nicolas; Obata, Yasuko; Moradian, Sam et al. (2013) Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis. J Dermatol Sci 72:296-303
Park, Kyungho; Elias, Peter M; Shin, Kyoung-Oh et al. (2013) A novel role of a lipid species, sphingosine-1-phosphate, in epithelial innate immunity. Mol Cell Biol 33:752-62
Goto-Inoue, Naoko; Hayasaka, Takahiro; Zaima, Nobuhiro et al. (2012) Imaging mass spectrometry visualizes ceramides and the pathogenesis of dorfman-chanarin syndrome due to ceramide metabolic abnormality in the skin. PLoS One 7:e49519
Park, Kyungho; Elias, Peter M; Oda, Yuko et al. (2011) Regulation of cathelicidin antimicrobial peptide expression by an endoplasmic reticulum (ER) stress signaling, vitamin D receptor-independent pathway. J Biol Chem 286:34121-30
Uchida, Yoshikazu; Cho, Yunhi; Moradian, Sam et al. (2010) Neutral lipid storage leads to acylceramide deficiency, likely contributing to the pathogenesis of Dorfman-Chanarin syndrome. J Invest Dermatol 130:2497-9

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