- The goal of this proposal is to understand better the factors that regulate hair loss, which is a major social concern associated with more common male-pattern baldness as well as more rare forms of alopecia and chemotherapy. To understand hair loss and to develop new therapies to prevent this condition, it is necessary to develop better understanding of the biology of the hair follicle, a unique structure that develops and matures mainly in prenatal skin, and cycles in the post-natal skin in a complex interaction of epithelium and mesenchyme. Once developed, the follicles undergo a cycle of renewal in three phases: telogen (resting), anagen (growth), and catagen (regression). This proposal focuses on the role of the Sonic hedgehog (Shh) signaling pathway on modulation of the hair-follicle cycle after birth. Shh function is associated with a complex pathway that includes Ptc (the Shh receptor), Smo (a G-protein coupled receptor that interacts with Ptc), a variety of signaling genes that include Wnt class proteins, and transforming growth factor-b family. Based on the known upregulation of Shh expression in the anagen phase of follicle growth, and preliminary data demonstrating that transient, adenovirus (Ad) gene transfer vector-mediated Shh expression induces anagen and robust hair growth in postnatal skin, the proposed studies are based on the hypothesis that transient (less than a week), enhanced Shh activity functions as a biologic switch that induces resting follicles to enter the anagen growth phase of the follicle cycle, with consequent hair growth. Experiments are proposed to evaluate two hypotheses in postnatal skin: (1) Transient imbalance of the Shh pathway in favor of Shh activity induces hair follicles to enter the anagen phase with consequent hair growth; and (2) for Shh to induce anagen, the enhanced expression of Shh must be in keratinocytes, and for the resulting follicle cycle to be normal, the enhanced expression must be transient (days), not persistent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046282-04
Application #
6632672
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$272,948
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Lou, Howard; Crystal, Ronald G; Leopold, Philip L (2005) Enhanced efficacy of cholesterol-minus sonic hedgehog in postnatal skin. Mol Ther 12:575-8
O'Connor, Timothy P; Crystal, Ronald G (2004) The Gordon Wilson lecture: using genetic medicine to regenerate diseased organs and protect against the hostile environment. Trans Am Clin Climatol Assoc 115:163-83
Bailey, Christopher J; Crystal, Ronald G; Leopold, Philip L (2003) Association of adenovirus with the microtubule organizing center. J Virol 77:13275-87
Bergstein, Ivan; Leopold, Philip L; Sato, Noboru et al. (2002) In vivo enhanced expression of patched dampens the sonic hedgehog pathway. Mol Ther 6:258-64
Sato, N; Leopold, P L; Crystal, R G (2001) Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia. J Natl Cancer Inst 93:1858-64
Strutz, F; Okada, H; Lo, C W et al. (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130:393-405
Strutz, F; Neilson, E G (1994) The role of lymphocytes in the progression of interstitial disease. Kidney Int Suppl 45:S106-10