Our long term goal is to elucidate the immunologic and genetic basis of alopecia areata (AA). Towards this end, we have recently developed a mouse model of the human disease. The exciting results of our initial experiments indicate that these mice have spontaneous hair loss that clinically resembles that of the human disease, and abnormal autoantibodies to hair follicles (HF), which again, are similar to those present in human AA. A strong collaboration has been forged between The Jackson Laboratory, where the mouse model was developed, and the NYU laboratory, where the immunological abnormalities were discovered. The specific goals of this joint proposal are to study (1) the role of HF autoantibodies in the pathogenesis of AA. This will involve: a) confirming that abnormal autoantibodies to HF are specifically associated with C3H/HeJ mice with AA; b) determining whether the presence of these antibodies precedes or follows the development of hair loss and whether these antibodies can induce alopecia when administered to unaffected animals; and c) characterizing the individual antigens defined by abnormal HF antibodies present in C3H/HeJ mice with alopecia, their relation to HF antigens implicated in the pathogenesis of AA in humans, and whether the expression of these antigens is genetically determined. (2) The genetic basis of murine AA. The AA phenotype in mice has an autosomal dominant pattern of inheritance with poor penetrance, as do some forms of human AA. An intercross and backcross strategy with C57BL/6J mice has identified putative linkage for the AA susceptibility locus. This approach will be repeated using an intersubspecific cross with Mus musculus castaneus (CAST/Ei) to generate a high resolution map. Using the Mouse Genome Database (MGD), candidate genes will be identified and investigated. Successful completion of this grant will further our understanding of the causes of AA and hopefully lead to an improved treatment for this common and disfiguring disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Moshell, Alan N
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Jackson Laboratory
Bar Harbor
United States
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Sundberg, John P; McElwee, Kevin J; Carroll, Joseph M et al. (2011) Hypothesis testing: CTLA4 co-stimulatory pathways critical in the pathogenesis of human and mouse alopecia areata. J Invest Dermatol 131:2323-4
Sun, Jing; Silva, Kathleen A; McElwee, Kevin J et al. (2008) The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results. Exp Dermatol 17:793-805
King Jr, Lloyd E; McElwee, Kevin J; Sundberg, John P (2008) Alopecia areata. Curr Dir Autoimmun 10:280-312
Logunova, Nadezda N; Viret, Christophe; Pobezinsky, Leonid A et al. (2005) Restricted MHC-peptide repertoire predisposes to autoimmunity. J Exp Med 202:73-84
Sundberg, John P; Silva, Kathleen A; Li, Renhua et al. (2004) Adult-onset Alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model. J Invest Dermatol 123:294-7
Everts, Helen B; King Jr, Lloyd E; Sundberg, John P et al. (2004) Hair cycle-specific immunolocalization of retinoic acid synthesizing enzymes Aldh1a2 and Aldh1a3 indicate complex regulation. J Invest Dermatol 123:258-63
Tang, L; Cao, L; Sundberg, J P et al. (2004) Restoration of hair growth in mice with an alopecia areata-like disease using topical anthralin. Exp Dermatol 13:5-10
Sundberg, John P; King Jr, Lloyd E (2003) Mouse alopecia areata models: an array of data on mechanisms and genetics. J Investig Dermatol Symp Proc 8:173-5
McElwee, K J; Silva, K; Boggess, D et al. (2003) Alopecia areata in C3H/HeJ mice involves leukocyte-mediated root sheath disruption in advance of overt hair loss. Vet Pathol 40:643-50
Freyschmidt-Paul, Pia; McElwee, Kevin J; Botchkarev, Vladimir et al. (2003) Fas-deficient C3.MRL-Tnfrsf6(lpr) mice and Fas ligand-deficient C3H/HeJ-Tnfsf6(gld) mice are relatively resistant to the induction of alopecia areata by grafting of alopecia areata-affected skin from C3H/HeJ mice. J Investig Dermatol Symp Proc 8:104-8

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