Despite different pathogenic mechanisms, most common hair growth disorders (androgenic alopecia and alopecia areata) are characterized by the development of hair follicle miniaturization with significant elongation of the resting stage, shortening of the growth stage of hair cycle, and hair loss. Molecular signals that trigger hair follicle transformation from resting to active growth and from active growth to the regression during postnatal development, in normal skin and in skin affected by hair growth disorders are still poorly understood. Noggin is a specific antagonist of bone morphogenic proteins 2 and 4 (BMP 2 and 4), members of TGF beta BMP superfamily. Noggin binds Bmp 2 and 4 with high affinity and prevents their interactions with BMP receptors. Noggin plays essential roles in controlling morphogenesis of ectodermal derivatives (neural tube, feather, hair follicle) and in regulating apoptosis during development. Noggin stimulates morphogenesis of ectodermal derivatives and downregulates BMP mediated apoptosis. Hypothesis: Noggin plays important roles in the initiation of new hair growth wave in postnatal skin and in the apoptosis driven hair follicle regression in normal skin and in skin affected by alopecia areata. Purpose: 1) Characterize expression of noggin, BMP 2 and 4, BMP receptors and BMP target genes during hair cycle in C5713L6 mice and in C3HHeJ mice affected by alopecia areata. 2) Define the roles for noggin and BMP 2 and 4 in hair growth control by pharmacologically manipulating hair cycle in normal C57BL6 mice and in C3HHeJ mice affected by alopecia areata. 3) Determine the in vivo function of noggin in the control of hair follicle growth by generating noggin-overexpressing mice using versican or K5 as promoters. 4) Characterize dynamics of alopecia areata development in C3HHeJ noggin transgenic mice induced by grafting C3HHeJ mouse skin affected by alopecia areata. 5) Analyze mechanisms of noggin and BMP 2 and 4 involvement in hair growth control by analyzing alterations in expression of their target genes in the experimental models mentioned above. Investigation of the in vivo functions of noggin and BMP 2 and 4 as putative modulators of hair follicle cycling in normal skin and in skin affected by alopecia areata is intended to provide new knowledge into hair cycle biology and could raise a possibility to explore BMP antagonists for the treatment of this disorder.
|Sharova, Tatyana Y; Poterlowicz, Krzysztof; Botchkareva, Natalia V et al. (2014) Complex changes in the apoptotic and cell differentiation programs during initiation of the hair follicle response to chemotherapy. J Invest Dermatol 134:2873-2882|
|Fessing, Michael Y; Sharova, Tatyana Y; Sharov, Andrey A et al. (2006) Involvement of the Edar signaling in the control of hair follicle involution (catagen). Am J Pathol 169:2075-84|
|Sharov, Andrey A; Sharova, Tatyana Y; Mardaryev, Andrei N et al. (2006) Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes. Proc Natl Acad Sci U S A 103:18166-71|
|Botchkarev, Vladimir A; Fessing, Michael Y (2005) Edar signaling in the control of hair follicle development. J Investig Dermatol Symp Proc 10:247-51|
|Sharov, Andrey A; Fessing, Michael; Atoyan, Ruzanna et al. (2005) Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway. Proc Natl Acad Sci U S A 102:93-8|
|Botchkarev, Vladimir A; Sharov, Andreij A (2004) BMP signaling in the control of skin development and hair follicle growth. Differentiation 72:512-26|
|Sharov, Andrei A; Weiner, Lorin; Sharova, Tatyana Y et al. (2003) Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation. EMBO J 22:2992-3003|