REACTIVE OXYGEN SPECIES AS MEDIATORS OF TGF-B1 ACTIONS

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DESCRIPTION (Adapted from the applicant's abstract) This is an application for additional research training for Dr. Victor J. Thannickal while he pursues accomplishment of a project that will allow him to be competitive for independent support. He has now spent two years in a research training fellowship, during which time he has identified the presence of a novel NADH oxidase on certain cell surfaces including that of the fibroblast which is important in the development of pulmonary fibrosis. Furthermore, he has found that this enzyme is stimulated by TGF-Bl, a cytokine whose presence has been associated with fibrosis and which is capable of enhancing the production of a macrophage chemoattractant and the autocrine production of TGF-B1 itself which may perpetuate the process. He theorizes that stimulation of H202 production by TGF-B1 may be a signaling event in the fibrotic process and wishes to evaluate this further with studies designed to: 1) assess enzymatic properties of the NADH oxidase; 2) evaluate possible related transduction pathways through studies of protein tyrosine phosphorylation; and 3) determine association with possible transcription pathways that activate M-CSF and TGF-B1 genes. Dr. Barry Fanburg will continue to sponsor and supervise his work. In addition to the daily mentored research by Dr. B. Fanburg and Dr. Thannickal will review his progress quarterly with a committee that includes Drs. Norman Krinsky, Irwin Arias and Brent Cochran of the Tufts University School of Medicine and will take relevant course work at the adjacent Sackler Graduate School of the Tufts University School of Medicine.