Cellular activation involves the advancement of cells along the cell cycle from the resting G0 state to the metabolically active G1 phase. This proposal focuses on the study of events occuring during this critical early G0/G1 period in normal and abnormal lymphocytes. The activation of T lymphocytes involves a series of complex intracellular events beginning at the cell membrane and culminating in DNA synthesis. The intracellular pathways by which these signals are transmitted to the nucleus are not clearly understood but can be divided into two major groupings. One includes the generation of inositol triphosphate which then stimulates a rise in intracellular calcium. The second group involves diacylglycerol which induces cellular activation without producing a rise in intracellular calcium. The production of these intracellular secondary messengers (Inositol triphosphate, diacylglycerol, and calcium) will be measured. The relationship and ability of these secondary messengers to activate genes will be investigated. The transcription of three genes associated with cellular activation, c-fos, c-myc and p53 will be studied in normal murine T cells and in an abnormal spontaneous mutant whose T cells fail to become activated by normal immunological stimuli. These abnormal T cells are the result of a single autosomal recessive mutant gene whose presence also causes severe autoimmune disease and early death. Patients with autoimmune diseases possess many of the same T cell activation abnormalities as these mutant mice, and therefore, any new insights gained from these studies might have implications for human disease and possibly lead to new therapeutic strategies.
