The immune response of B lymphocytes is regulated by antigen, a number of cytokines and perhaps by physical interactions with T cells and accessory cells. In some cases, regulatory species appear to direct different biologic responses by the same B cell. To accomplish this, the B cell presumably must utilize different biochemical mechanisms to convey, or transduce, information generated on the outside of the cell to the inside. Our long term interests lie in the molecular basis of this differential signaling. An ideal model system for analysis of this question exploits the recently described ability of virtually all normal, small B cells to respond to both mIg crosslinking ligands and B cell stimulatory factor 1 (BSF1). It has recently become clear that in small B cells, mIg crosslinking mediated signals are transduced via polyphosphoinositide hydrolysis, Ca++ mobilization and protein kinase C activation. Our preliminary evidence suggests that BSF1 mediated signals may be transduced by a different mechanism. We propose to examine this possibility further and to define the biochemical basis of signal transduction following BSF1 binding by small B cells. Specifically, we propose to: 1. determine whether BSF1 signal transduction occurs via a polyphosphoinositide hydrolysis cascade, 2. determine whether BSF1 modulates the transduction cascade induced by mIg crosslinking ligands, 3. analyze the role of specific """"""""second messenger"""""""" regulated protein kinases in BSF1 mediated signal transduction, and 4. utilize pharmacologic agents to define the cause and effect relationship between early biochemical events defined in Specific Aims 1-3 and later biologic responses to BSF1. For our studies we will use a combination of flow-cytometric and radio biochemical assays. Results of these studies should contribute significantly to our understanding of the molecular basis of regulation of lymphocyte growth and differentiation.
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