The long-term goal of this project is to better understand skin regeneration following wounding in adults. We discovered that after a full thickness wound on the back skin of an adult mouse, hair follicles form de novo. These new follicles reestablish their stem cell niche, produce hair, and cycle. This regeneration resembles embryonic hair follicle development morphologically and molecularly, and occurs several days after wound closure and reepithelialization. Inhibition of wnt prevents hair follicle neogenesis, while wnt overexpression enhances hair follicle formation. The major goal of this grant is to further characterize hair follicle neogenesis and understand the molecular signals controlling this phenomenon. We hypothesize that adult mammals, including humans, have the capacity to regenerate epidermal adnexal structures, such as hair follicles and sebaceous glands, and that this regeneration can be enhanced or inhibited by manipulating pathways known to be important for hair follicle development.
Our aims are to study the effects of aging, hair cycle, minimum stimulus required for neogenesis, and whether neogenesis occurs in human skin grafted to immunodeficint mice. We will also define the role of adult stem cell populations in the skin for their ability to contribute to hair follicle neogenesis. Lastly, we will examine the role of growth factors known to be necessary for hair follicle development in follilce neogenesis. We will use global gene expression patterns to assist with our analysis and effort to discern the molecular pathways necessary for neogenesis so that we can eventually manipulate these pathways to improve wound healing. We will use transgenic and knockout mouse technology to evaluate the function of candiadate genes necessary for hair follicle regeneration. Our results should have major implications for understanding skin biology and developing future treatments for wounds, alopecia and other degenerative skin disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR055309-01
Application #
7303193
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2007-07-12
Project End
2012-06-30
Budget Start
2007-07-12
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$338,625
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lim, Chae Ho; Sun, Qi; Ratti, Karan et al. (2018) Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing. Nat Commun 9:4903
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
Ali, Niwa; Zirak, Bahar; Rodriguez, Robert Sanchez et al. (2017) Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation. Cell 169:1119-1129.e11
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
Xie, Lin; Yang, Ruifeng; Liu, Shujing et al. (2016) TR3 is preferentially expressed by bulge epithelial stem cells in human hair follicles. Lab Invest 96:81-8
Yang, Guangrui; Chen, Lihong; Grant, Gregory R et al. (2016) Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival. Sci Transl Med 8:324ra16
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
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-461
Yang, Ruifeng; Zheng, Ying; Li, Ling et al. (2014) Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors. Nat Commun 5:5807
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 134:538-540

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