The candidate, Anita C. Gilliam, is a junior faculty member on tenure track in Dermatology at Case Western Reserve University (CWRU), where she is developing a research career in molecular mechanisms of autoimmune disease. The proposed work draws on her experience in molecular biology and cutaneous immunobiology, and requests support for a mentored Clinical Scientist Development Award to acquire new expertise in monocyte biology under the mentorship of Dr. Kevin D. Cooper (Dermatology). The research environment, resources, and opportunities for career development at CWRU are superb, with CWRU School of Medicine recently listed as one of the top 10 research institutions in the country, and the Department of Dermatology as the top US program in NIH funding. The candidate's immediate goals are to develop the animal model in the proposed work into a vehicle useful for testing of interventions in scleroderma; long term goals are to develop the science of cutaneous monocyte biology and gene transfer in autoimmune disease as an independently funded investigator in an outstanding research environment. The proposal involves the study of systemic sclerosis/scleroderma, a chronic autoimmune disease of unknown etiology characterized by altered humoral and cell-mediated immunity, and excessive deposition of collagen in viscerae and skin, which is thought to be driven by activated monocytes making TGFbeta. We have characterized a very promising murine model for scleroderma that recapitulates many important features of scleroderma. Hypothesis: Monocytes are critical effector cells in Scl GVHD. TGF -beta1 is a major fibrogenic cytokine driving skin fibrosis in mice with Scl GVHD; TGF-beta2 and TGF-beta3 play minor if any roles in this cutaneous fibrosis. Skin fibrosis can be inhibited by: 1) antibodies to TGF-beta, 2), and latency associated peptide (LAP), a naturally occurring antagonist for TGF-beta.
Specific Aim 1 : To investigate the mechanism and sequence of early critical events leading to skin fibrosis in animals with Scl GVHD to better understand the pathophysiology of fibrosing disease and to devise novel focused interventions. Establishing the critical parameters of monocyte influx into skin, production of fibrogenic TGFbeta, and upregulation of proalpha(I) collagen mRNA synthesis provides a foundation for in vivo focused interventions.
Specific Aim II : To further characterize in vivo interventions that inhibit TGFbeta1 in Scl GVHD. We have shown in preliminary experiments that TGF-beta LAP and antibodies to TGF-beta inhibit skin fibrosis in animals with Scl GVHD. Further characterization of these observations have high relevance to our understanding of basic monocyte biology, to the TGFbeta-driven fibrosing process in the animal model and in the autoimmune disease scleroderma, and potentially to the treatment of scleroderma and human graft versus host disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR002082-03
Application #
6512005
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Moshell, Alan N
Project Start
2000-07-14
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$122,040
Indirect Cost
Name
Case Western Reserve University
Department
Dermatology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Zhang, Alexandra Y; Wu, Caiyun; Zhou, Lixin et al. (2006) Transduced monocyte/macrophages targeted to murine skin by UV light. Exp Dermatol 15:51-7
Hershko, Klilah; Hull, Cheryl; Ettefagh, Leila et al. (2004) A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodeling? J Cutan Pathol 31:262-5
Zhang, Yan; McCormick, Laura L; Gilliam, Anita C (2003) Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 121:713-9
Ng, Pamela C; Barzilai, David A; Ismail, Sahar A et al. (2003) Evaluating invasive cutaneous melanoma: is the initial biopsy representative of the final depth? J Am Acad Dermatol 48:420-4
Zhang, Yan; Gilliam, Anita C (2002) Animal models for scleroderma: an update. Curr Rheumatol Rep 4:150-62
Zhang, Yan; McCormick, Laura L; Desai, Snehal R et al. (2002) Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 168:3088-98
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