The hypoxia inducible factor HIF-1 alpha is ubiquitously expressed but undergoes proteosomal degradation under normal oxygen conditions. However, because the skin is naturally hypoxic, HIF-1 alpha is stably expressed and detectable by immunohistochemistry in the epidermis and hair follicle. We have observed that mice in which HIF-1 alpha has been deleted postnatally develop skin lesions that are characterized by epidermal thickening and hair loss. Recent research has shown that HIF-1 alpha regulates p21 expression in keratinocytes, and correlates with cell cycle arrest in cultured keratinocytes in vitro. This proposal will test the following hypothesis: HIF-1 alpha plays an essential role in regulating keratinocyte proliferation and differentiation in vivo in a c-Myc dependent manner. To test this hypothesis, we will (1) determine the role of HIF-1 alpha in the epidermis and (2) determine the mediators of epidermal HIF-1 alpha activity, focusing on c- Myc. The proposed experiments will allow us to conduct initial investigations into the role of HIF-1 alpha in keratinocytes. The overall goal of the studies is to understand the degree to which HIF-1 alpha regulates biological processes in physiological settings such as the epidermis, as well as the mechanisms by which it acts, and how this phenomenon contributes to skin growth and differentiation in both homeostasis and disease.

Public Health Relevance

Oxygen sensitive hypoxia inducible factors (HIFs) participate in the transcriptional response to low oxygen availability and thus regulate important biological processes in development, homeostasis, and disease. This project will provide fundamental insight into how HIF-1 alpha controls keratinocyte behavior, and could suggest new strategies for promoting skin regeneration and treating hyperproliferative skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR057217-05
Application #
8499267
Study Section
Special Emphasis Panel (ZAR1-KM-D)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$64,351
Indirect Cost
$24,132
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-61
Hammers, Christoph M; Chen, Jing; Lin, Chenyan et al. (2015) Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J Invest Dermatol 135:742-9
Thangapazham, Rajesh L; Klover, Peter; Li, Shaowei et al. (2014) A model system to analyse the ability of human keratinocytes to form hair follicles. Exp Dermatol 23:443-6
Cho, Michael Jeffrey; Lo, Agnes S Y; Mao, Xuming et al. (2014) Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat Commun 5:4167
Rangel, Javier R; Chung, Yoonjie; Rosenbach, Misha et al. (2014) Expression of Notch signaling components in cutaneous foreign body and sarcoidal granulomas and fusing macrophages. Am J Dermatopathol 36:409-13
Rashighi, Mehdi; Agarwal, Priti; Richmond, Jillian M et al. (2014) CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med 6:223ra23
Mao, Xuming; Li, Hong; Sano, Yasuyo et al. (2014) MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol 134:68-76
Guan, Hancheng; Nuth, Manunya; Zhukovskaya, Natalia et al. (2014) A novel target and approach for identifying antivirals against molluscum contagiosum virus. Antimicrob Agents Chemother 58:7383-9
Suzuki, Daisuke; Leu, N Adrian; Brice, Angela K et al. (2014) Expression analysis of Dact1 in mice using a LacZ reporter. Gene Expr Patterns 15:21-30
Thangapazham, Rajesh L; Klover, Peter; Wang, Ji-an et al. (2014) Dissociated human dermal papilla cells induce hair follicle neogenesis in grafted dermal-epidermal composites. J Invest Dermatol 134:538-40

Showing the most recent 10 out of 37 publications