The terms """"""""apoptosis"""""""" or """"""""programmed cell death"""""""" are sometimes used as if they are the result of one single pathway. And the 'Pathway' in mind more often than not is the prototype Fas/CD95-receptor pathway. However, there are many distinct ways to initiate cell death, and the downstream effector and regulatory mechanisms of death pathways may be different. This study will explore two aspects of B lymphocyte death: 1) how the pathway of B cell receptor (BCR-induced death compares to the well-defined Fas pathway and 2) how the B cell surface molecule CD22 regulates this BCR pathway. Signaling through the BCR can lead to clonal expansion of specific B cells, clonal inactivation (anergy) or clonal elimination/death. Whether or not BCR ligation leads to proliferation, anergy or death depends on the stage of B cell and the activity of co- receptors such as CD22. The investigators have found that members of the MAP family of protein kinases (MAPK family) including the stress- activated/Jun protein kinases (JNKs) and p38 MAPK regulate B cell death and anergy. They also found that B cells in CD22-deficient mice have a short life span and are more susceptible to BCR-induced cell death. The goal of this project is to define how members of the MAPK family of kinases and CD22 regulate B cell fate. A combination of biochemical and genetic approaches will be taken to test the hypotheses that: 1) CD22 regulates B cell fate through distinct """"""""functional domains"""""""" within its cytoplasmic tail which recruit and activate the Syk protein tyrosine kinase (PTK) and the SHP1 protein tyrosine phosphatase (PTPase); 2) BCR- induced cell death is mediated via a death pathway distinct from the Fas-mediated death pathway and requires new gene transcription of death pathway genes; and 3) a specific subset of short-lived B cells are dysregulated in CD22 -/- mice and that these B cells have a dysregulated BCR death pathway. This work will provide new insights into how the fate of B lymphocytes is regulated, which may be pertinent to understanding origins of leukemias, lymphomas and autoimmune diseases.
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