Richard J. Bram, M.D., Ph.D.

Signal transduction - Our research stems from an interest in molecular signaling events that control cellular behavior in activation of the immune system and in neoplastic transformation.

Ongoing projects include: Studies on the mechanism of action of CAML, an intracellular signal-transduction protein; characterization of TACI, a lymphocyte-specific TNFR family member; and identification of other novel proteins capable of regulating signals important in cell growth, function, or transformation.

Specific Research Topics

Stimulation of cells through the T cell receptor (TCR) activates a series of carefully regulated signals which can lead to explosive cell growth and activation of immune system functions. Under specific conditions, however, these signals can instead initiate programmed cell death and eradication of lymphocytes. Recent evidence suggests that disruption of this delicate balance between lymphocyte proliferation and death may contribute to immune system disease (immunodeficiency or autoimmunity) and neoplastic transformation (leukemia and lymphoma). Because of the central importance of these signals, we have searched to identify novel proteins that can modulate such signal transduction pathways, using lymphocyte activation assays as secondary screens for potentially interesting molecules.

The potent immunosuppressive drug cyclosporin A blocks Ca2+-dependent signals emanating from the TCR, through its interaction with cyclophilin and calcineurin. We used cyclophilin as bait in a yeast two-hybrid screen, and identified a novel gene we call CAML (for Calcium Modulating cyclophilin Ligand). CAML is a ubiquitous intracellular integral membrane protein, which appears able to initiate intracellular Ca2+ influx, a key activator of lymphocytes. Current work is focused on determining the definitive role of CAML in development and function of the immune system. Toward that end, we have generated a CAML knock-out mouse, which shows a severe phenotype due to loss of the gene. Future studies in this project will aim to elucidate the precise role of the protein through the analysis of total and conditional knock-out CAML alleles in mice, combined with further in vitro studies on T cell activation signaling events.

A second project focuses on the novel Tumor Necrosis Receptor Family member TACI, which was discovered through its ability to physically interact with CAML. TACI is restricted in expression pattern to B lymphocytes and activated T cells, and is postulated to act as a co-stimulatory cell surface receptor. On-going analysis of TACI, using mouse knock-out and protein-protein interaction technology, is geared to understanding the role of the protein in B cell growth and function, with an eye toward possible clinical applications in diagnosis or treatment of lymphoma.