The long-term goal of this research program is to delineate mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in B-lymphocytes and to understand how these same mechanisms influence the fate of activated B-cells. A link exists between the supply of phosphatidylcholine (PtdCho), the most abundant phospholipid in cellular membranes, and unfolded protein response (UPR) signaling pathway. XBP1(S), a transcription factor generated by the UPR, is required for normal antibody production, maximal increases in total PtdCho and ER expansion in stimulated B-cells. Another UPR transcription factor, ATF61, also has the ability to induce PtdCho synthesis and ER expansion. Deletion of CCT1, the rate-limiting enzyme in PtdCho synthesis, markedly diminishes PtdCho production in activated B-cells. This correlates with accelerated induction of XBP1(S) and IgM secretion, but little production of other antibody isotypes. Therefore, we hypothesize that PtdCho supply can influence the fate of activated B-cells by interfacing with the UPR to promote PtdCho synthesis and drive differentiation of antibody-secreting B-cells. The project will focus on four specific aims and utilize gene knockout mouse models, cell culture systems and a combination of molecular, biochemical and cellular techniques.
In aim 1, experiments will address the mechanism by which XBP1(S) up-regulates PtdCho supply in activated B-cells.
In aim 2, studies will assess the contributions of ATF61 to the regulation of PtdCho synthesis and ER expansion in activated B-cells.
In aim 3, experiments will address how a limited PtdCho supply at distinct stages of the B-cell response affects B-cell function and fate in vivo.
In aim 4, the mechanism linking PtdCho supply to UPR activation will be explored. Experiments will assess how reduced levels of PtdCho affect ER function and protein transport in the secretory pathway. Antibody-mediated autoimmune disorders such as lupus and B-cell cancers like multiple myeloma are devastating diseases, underscoring the need to identify novel regulatory mechanisms in B-cells that might provide new targets for drug design. The UPR is also involved in many other physiologically significant processes including tumor progression and proper function of the pancreas and liver. Understanding how the UPR works in normal cellular processes is necessary for rational exploration of drugs to modulate this pathway in disease states.
Normal B-cells in the body help fight infection, but B-cells that malfunction can cause life- threatening diseases like cancer. In this research, processes that control B-cell function are being studied. The results may lead to new treatments for diseases caused by faulty B-cells.
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