The long term goal of this project is to better understand epithelial stem cell biology. Epithelial stem cells are responsible for the regeneration of self-renewing tissues such as epidermis, hair follicle, and cornea. We originally identified putative epithelial stem cells in the bulge of the hair follicle. We then isolated a keratin 15 promoter that targets bulge cells in transgenic mice. The K15 promoter allowed for the isolation, lineage analysis and molecular characterization of hair follicle stem cells. We showed, that bulge cells have properties of stem cells, and isolated bulge cells can reconstitute hair follicles, epidermis and sebaceous glands. We have now identified a number of genes which we hypothesize maintain the stem cell phenotype. In this grant application we will: 1. evaluate whether genes upregulated in the bulge cells are important for maintaining the hair follicle stem cell phenotype by: a. overexpressing candidate genes in non-hair follicle stem cells of transgenic mice, and then testing whether these cells behave as hair follicle stem cells. b. blocking candidate gene pathways specifically in the bulge cells using our Kl5CrePrl mice to delete or overexpress genes specifically in the bulge cells. 2. determine if genes downregulated in telogen bulge cells are involved in stem cell activation and/or lineage determination by: a. generating inducible transgenic mice in which candidate genes are over-expressed in bulgecells using an RU486 inducible system, and b. deleting candidate """"""""bulge activation"""""""" or lineage determining genes specifically in bulge cells and their progeny using theKlSCrePR l mice. 3. develop means for isolating and characterizing human hair follicle stem cells. a. We will establish whether genes identified in mouse bulge are also expressed in human bulges. b. We will delineate hair follicle stem and progenitor cells within both the mouse and human hair follicle based on cell surface protein expression patterns. These distinct subpopulations of cells within the hair follicle will be isolated by fluorescent activated cell sorting, and their stem cell nature, gene expression patterns and functional characteristics will be discerned. Patients with alopecia, hair shaft disorders, basal cell carcinoma, hair follicle tumors, or chronic wounds could potentially benefit from this research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046837-10
Application #
7640613
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2000-04-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2009
Total Cost
$321,974
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Gay, Denise; Kwon, Ohsang; Zhang, Zhikun et al. (2013) Fgf9 from dermal ?? T cells induces hair follicle neogenesis after wounding. Nat Med 19:916-23
Garza, Luis A; Liu, Yaping; Yang, Zaixin et al. (2012) Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med 4:126ra34
Garza, Luis A; Yang, Chao-Chun; Zhao, Tailun et al. (2011) Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest 121:613-22
Yang, Chao-Chun; Cotsarelis, George (2010) Review of hair follicle dermal cells. J Dermatol Sci 57:2-11
Ito, Mayumi; Liu, Yaping; Yang, Zaixin et al. (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11:1351-4
Morris, Rebecca J; Liu, Yaping; Marles, Lee et al. (2004) Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22:411-7
Liu, Yaping; Lyle, Stephen; Yang, Zaixin et al. (2003) Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J Invest Dermatol 121:963-8
Xu, Xiaowei; Lyle, Stephen; Liu, Yaping et al. (2003) Differential expression of cyclin D1 in the human hair follicle. Am J Pathol 163:969-78