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 #
5P30AR057217-04
Application #
8376529
Study Section
Special Emphasis Panel (ZAR1-KM-D)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$68,922
Indirect Cost
$25,846
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Xu, Mingang; Horrell, Jeremy; Snitow, Melinda et al. (2017) WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nat Commun 8:15397
Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752
Hammers, Christoph M; Stanley, John R (2016) Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. Annu Rev Pathol 11:175-97
Cho, Michael Jeffrey; Ellebrecht, Christoph T; Hammers, Christoph M et al. (2016) Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6. J Immunol 197:1065-73
Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84
Geherin, Skye A; Gómez, Daniela; Glabman, Raisa A et al. (2016) IL-10+ Innate-like B Cells Are Part of the Skin Immune System and Require ?4?1 Integrin To Migrate between the Peritoneum and Inflamed Skin. J Immunol 196:2514-2525
Lo, Agnes S; Mao, Xuming; Mukherjee, Eric M et al. (2016) Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 11:e0156800
Gay, Denise L; Yang, Chao-Chun; Plikus, Maksim V et al. (2015) CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis. J Invest Dermatol 135:45-55
Agarwal, Priti; Rashighi, Mehdi; Essien, Kingsley I et al. (2015) Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo. J Invest Dermatol 135:1080-1088
Lin, Ping; Mobasher, Maral E; Hakakian, Yasaman et al. (2015) Differential requirements for H/ACA ribonucleoprotein components in cell proliferation and response to DNA damage. Histochem Cell Biol 144:543-58

Showing the most recent 10 out of 94 publications