Adult stem cells are the basic building blocks for wound repair and regeneration. Understanding how to stimulate their growth and development is critical to advancing regenerative medicine. Our laboratory studies adult stem cells in the hair follicle because they are accessible and divide at specific developmental ages. Recently, activating mutations in the RAS signaling pathway have been found in children with Costello and cardiofaciocutaneous (CFC) syndromes. These syndromes are associated with multiple skin defects that appear to affect the proliferation and differentiation of skin stem cells. We have recently developed several mouse models, which develop many of the same skin abnormalities as Costello and CFC patients, including excess skin production and hair loss. We propose to use our mouse models to 1) investigate the basis of RAS- induced hair cycle defects, 2) determine the effect of RAS on adult stem cell proliferation, and 3) identify the downstream pathways that cause these defects. By understanding the function of RAS signaling in adult stem cells of the skin, new therapies could be developed to improve organ regeneration and wound repair.

Public Health Relevance

Adult stem cells are the basic building blocks for wound repair and regeneration. We are studying the role of RAS in regulating adult stem cell proliferation and differentiation. As an experimental model, we will study how RAS affects adult stem cells of the hair follicle during regeneration and wound repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056667-05
Application #
8461908
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$282,477
Indirect Cost
$99,644
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Krishnaswami, Suguna R; Kumar, Shantanu; Ordoukhanian, Phillip et al. (2015) Fate and plasticity of the epidermis in response to congenital activation of BRAF. J Invest Dermatol 135:481-9
Mukhopadhyay, Anandaroop; Krishnaswami, Suguna Rani; Cowing-Zitron, Christopher et al. (2013) Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development. Dev Biol 373:373-82
Hamilton, Bruce A; Yu, Benjamin D (2012) Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 8:e1002644
Mukhopadhyay, Anandaroop; Krishnaswami, Suguna R; Yu, Benjamin D-Y (2011) Activated Kras alters epidermal homeostasis of mouse skin, resulting in redundant skin and defective hair cycling. J Invest Dermatol 131:311-9
Lefkowitz, Gloria K; Mukhopadhyay, Anandaroop; Cowing-Zitron, Christopher et al. (2011) The post-apoptotic fate of RNAs identified through high-throughput sequencing of human hair. PLoS One 6:e27603