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. ? ? ? ?
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