My career goal is to become an investigator in an academic medical center performing basic and translational research of rheumatic diseases. Building on my previous experiences, I herein propose a comprehensive career development plan that combines mentored research with research seminars, didactic scientific and biostatistical coursework, training in research integrity, and independent scientific review that lead to independence during the time of this award. The proposed research training will be under the mentorship of Dr. John D. Reveille at the University of Texas Health Science Center at Houston (UTHSC) and co-mentorship of Dr. Michael Brenner at Brigham and Women's Hospital and Harvard Medical School and Dr. Michael R. Blackburn at UTHSC. The research proposal extends on our previous work describing the expression of cadherin-11 (cad-11) on human fibroblast-like synoviocyte (FLS). The proposal extends my own work of the initial characterization of cad-11 on mouse FLS and its role in the development of synovial inflammation. We hypothesize that cad-11 regulates FLS inflammatory cytokine and chemokine production and cadherin-11 alters the regulation of FLS-dependent macrophage chemotaxis and cytokine production. We will investigate the role of cad-11 in the regulation of FLS production of inflammatory cytokines and chemokines. Furthermore, we will determine the role of cad-11 in modulating the ability of FLS to recruit and regulate cytokine produciton by macrophages. We will perform in vitro analyses using standard cellular and molecular immunologic techniques as well as an innovative 3-dimensional micromass organ culture system. The use of FLS from wild-type and cad-11 null mice provides a direct comparison of cell types that will reveal the differences imparted by cad-11, which will be confirmed by blocking the expression and function of cad- 11 with monoclonal antibodies, recombinant cadherin-11 fusion protein, and siRNA. Finally, in Aim 3, we will investigate the cad-11 dependent changes in FLS during synovial inflammation in the KBxN serum transfer model of inflammatory arthritis using immunohistochemistry and a novel strategy to isolate fresh FLS from synovium. Although each individual assay provides a narrow picture of the role of cad-11 in arthritis, in their aggregate, these experiments will bring the role of cadherin-11 on FLS to a significant level of understanding and importance in synovial biology with relevance to inflammatory arthritis. ? ? ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
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Pedroza, Mesias; Le, Thuy T; Lewis, Katherine et al. (2016) STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J 30:129-40
Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert et al. (2014) Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol 66:1010-21
Schneider, Daniel J; Wu, Minghua; Le, Thuy T et al. (2012) Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-? production and epithelial to mesenchymal transition. FASEB J 26:503-12
Wu, Minghua; Schneider, Daniel J; Mayes, Maureen D et al. (2012) Osteopontin in systemic sclerosis and its role in dermal fibrosis. J Invest Dermatol 132:1605-14
Carmona, F David; Gutala, Ramana; SimeĆ³n, Carmen P et al. (2012) Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis. Ann Rheum Dis 71:114-9
Agarwal, Sandeep K; Wu, Minghua; Livingston, Christopher K et al. (2011) Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Ther 13:R3
Barnes, Jammie; Agarwal, Sandeep K (2011) Targeting STAT4 in systemic sclerosis: a promising new direction. Expert Rev Clin Immunol 7:445-8
Rueda, B; Gourh, P; Broen, J et al. (2010) BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Ann Rheum Dis 69:700-5
Arnett, Frank C; Gourh, Pravitt; Shete, Sanjay et al. (2010) Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 69:822-7
Radstake, Timothy R D J; Gorlova, Olga; Rueda, Blanca et al. (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42:426-9

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