This Program Project brings together investigators from a variety of disciplines who are focusing their divergent backgrounds on the regulation of keratinocyte differentiation. These workers will exploit in vitro and in vivo models, both human and murine, in which keratinocyte differentiation, including permeability barrier formation, can be manipulated precisely. Project #1 will evaluate the role of cornified envelope-associated proteins in permeability barrier function, utilizing a variety of human diseases due to specific mutations in such proteins as well as mouse models in which such proteins or their presumptive regulators have been genetically altered. Project #2 will investigate the role of protein kinase C in mediating calcium regulated differentiation, seeking in this pathway the mechanism by which calcium fails to stimulate differentiation in transformed keratinocytes. Project #3 will explore the role of the EnaC channel in mediating calcium- induce differentiation, investigating the importance of three major channel subunits for different stages of differentiation. Project #4 will focus on the role of omega-hydroxy ceramides in the formation of the lipid-bound envelope and for barrier function, and the role of the omega hydroxylase in the formation of these unique lipid constituents of the stratum corneum. Project #5 will extend prior observations that PPARalpha agonists promote epidermal differentiation by exploring both the molecular regulation of PPARalpha expression, and the importance of PPARalpha, using both keratinocyte cultures and PPARalpha knockout mice. The Cell Culture/Tissue Preparation Core whose activity is essential for the progress of all projects, will continue to provide advice as well as cells and organ cultures to the investigators. The Microscopy and Molecular Histology Laboratory (Morphology Core) will play an increasingly important role as in situ hybridization and immunolocalization at the light and electron microscopic level are utilized by all of the projects. Each investigator will rely upon other members of the group for ideas and specific collaborations, which will broaden the scope, productivity, and depth of each project. This synergy will be fostered by bi-weekly research meetings, an Outside Speakers Program, and the input of our Research Advisory Group. This proposal, then represents a continuation a continuation a continuation of our ongoing, successful effort at building a cohesive, interdisciplinary group aimed at unraveling the regulation of keratinocyte/epidermal differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR039448-14
Application #
6532946
Study Section
Special Emphasis Panel (ZAR1-BHD-B (M1))
Program Officer
Moshell, Alan N
Project Start
1988-07-15
Project End
2003-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
14
Fiscal Year
2002
Total Cost
$1,442,800
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Bikle, Daniel D (2016) Extraskeletal actions of vitamin D. Ann N Y Acad Sci 1376:29-52
Bikle, Daniel D; Oda, Yuko; Tu, Chia-Ling et al. (2015) Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer. J Steroid Biochem Mol Biol 148:47-51
Bikle, Daniel D (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 21:319-29
Bikle, Daniel D (2014) Vitamin D and cancer: the promise not yet fulfilled. Endocrine 46:29-38
Bikle, Daniel D (2014) The vitamin D receptor: a tumor suppressor in skin. Adv Exp Med Biol 810:282-302
Tu, Chia-Ling; Bikle, Daniel D (2013) Role of the calcium-sensing receptor in calcium regulation of epidermal differentiation and function. Best Pract Res Clin Endocrinol Metab 27:415-27
Jiang, Yan J; Kim, Peggy; Uchida, Yoshikazu et al. (2013) Ceramides stimulate caspase-14 expression in human keratinocytes. Exp Dermatol 22:113-8
Bikle, Daniel D (2012) Vitamin D and the skin: Physiology and pathophysiology. Rev Endocr Metab Disord 13:3-19
Bourguignon, L Y W; Earle, C; Wong, G et al. (2012) Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 31:149-60
Tu, Chia-Ling; Crumrine, Debra A; Man, Mao-Qiang et al. (2012) Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function. J Invest Dermatol 132:2350-2359

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