Therapeutic options for granulomatous disease are limited by an incomplete understanding of granuloma pathogenesis. The role of granuloma matrix in granuloma formation is unknown. Early T lymphocyte activation-1/Osteopontin, is an RGD containing matrix protein that is expressed in early cell mediated immune responses and modulates T cell and monocyte function in vitro. As initial granuloma formation is dependent on T cell:monocyte interactions, it is hypothesized that Eta- 1/Opn plays a role in granuloma development by regulating the early recruitment, activation and cytokine production of T cells and monocytes. The work proposed in this grant will characterize the ability of Eta-1/Opn to regulate T cell and monocyte migration, adhesion and cytokine production in vitro. Based on these studies, the in vivo role of Eta-l/Opn will be determined by inducing synchronous pulmonary granulomas in Eta-1/Opn deficient (knockout) and Eta-1/Opn over-expressing (lung specific transgenic) mice. The research training plan includes formal course work, bench research and clinical activities and will allow the investigator to gain expertise in a broad range of experimental techniques including basic studies of cellular immunology, molecular biology, histopathology, and animal models of disease. An experienced advisory committee will regularly review the progress of the investigator and the institutional environment is well equipped to facilitate the proposed experiments. The investigator will participate in a broad range of research, clinical and ethics seminars provided by the institution and attend national immunology meetings and symposia relevant to granuloma formation. The goal of the investigator is to acquire conceptual and technical skills in preparation for an independent research career in academic pulmonary immunology. Understanding early determinants and the role of matrix in granuloma development will provide basic insights into granuloma pathogenesis and may contribute to novel therapeutic approaches to granulomatous disease.
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| Li, Xinfang; O'Regan, Anthony W; Berman, Jeffrey S (2003) IFN-gamma induction of osteopontin expression in human monocytoid cells. J Interferon Cytokine Res 23:259-65 |
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| O'Regan, A W; Hayden, J M; Body, S et al. (2001) Abnormal pulmonary granuloma formation in osteopontin-deficient mice. Am J Respir Crit Care Med 164:2243-7 |
| Denhardt, D T; Noda, M; O'Regan, A W et al. (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107:1055-61 |
| O'Regan, A W; Nau, G J; Chupp, G L et al. (2000) Osteopontin (Eta-1) in cell-mediated immunity: teaching an old dog new tricks. Immunol Today 21:475-8 |
| O'Regan, A; Berman, J S (2000) Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol 81:373-90 |
