CYCLOPHILIN C FUNCTION

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DESCRIPTION (Adapted from applicant's abstract) Cyclophilin C (cyp C) is a member of a highly conserved and growing family of cyclosporine A (CsA) binding proteins found in bacteria, unicellular organisms and all plant and animal species tested. These ubiquitous proteins, which represent 0.1% to 0.4% of total cellular protein remain enigmatic. Studies utilizing cyp C were the first to identify calcineurin (CN) as the target of the immunosuppressant CsA, and analogous studies with FKBP-12 rapidly demonstrated that CN was a common downstream target of both CsA and FK506. With these results, key portions of his Ph.D. work, he reluctantly put down his pipette in 1992, completed his M.D. training and in 1993 began Pediatric Internship and Residency at The Children's Hospital in Boston. While he was doing admissions, others were making submissions--a tremendous amount of work has followed his initial observations regarding the role of CN in T cell activation. Still, upon returning to the lab as a fellow in Pediatric Heme/Onc it has become clear that much remains to be learned regarding the function of cyp C (and cyclophilins in general) in the absence of exogenous drugs. Experiments aimed at elucidating the function of murine cyp C, and, by inference, the function of these ancient and ubiquitous proteins are outlined. The specific aims include the characterization of the murine cyp C gene; an analysis of promoter/enhancer elements leading to tissue specific expression (bone marrow stroma, renal tubular cells at the corticomedullary junction, ovarian stromal cell and tesucular interstitial cells) and IL-1 induction of cyp C; the generation of cyp C -/- mice containing a green fluorescent protein transgene under control of the cyp C locus; and analysis of determinants of cyp C intracellular localization. GFP marking of cells with an active cyp C promoter (both cyp C +/- and -/- cells) will facilitate experiments to directly test biologic functions of cyp C (if -/- animals are viable). GFP marking of bone marrow stroma will allow both the identification of stromal cell precursors during development and direct testing of the importance of such cells in transplantation models. The facilities and staff at the Dana Farber, in combination with the rich intellectual resources afforded by proximity to Harvard and MIT, provide an ideal environment for carrying out this program of research which is designed to advance Dr. Friedman's training, integrate his interests in hematology and cyclophilin biology, and facilitate his transition towards a future as an independent investigator. (End of Abstract)