The long-term goal of this application is to identify molecular targets for drug development against autoimmune and immune-deficient diseases. TALL-1 is a recently identified member of the tumor necrosis factor (TNF) ligand family that stimulates B-cell proliferation and secretion of immunoglobulins. Overexpression of TALL-1 in mice leads to autoimmune-like manifestations, such as increased number of mature B-cells, splenomegaly, anti-DNA antibodies, and nephritis. It has been shown that BCMA, an orphan receptor of the TNF receptor family that is specifically expressed by B-cells, is a receptor for TALL-1. The goal of this application is to investigate the molecular mechanisms of intracellular signaling triggered by the TALL-1/BCMA ligand/receptor pair. To this end, three specific aims are proposed.
In specific aim 1, yeast two-hybrid screening and/or biochemical purification experiments will be performed to identify BCMA-associated signaling proteins.
In specific aim 2, immunoprecipitation/purification experiments will be performed to identify TALL-1-activated tyrosine kinases and their substrates.
In specific aim 3, cDNA subtractive hybridization experiments will be performed to identify genes transcriptionally regulated by TALL-1 stimulation. All the genes identified in the three specific aims will be functionally characterized by various approaches. These studies are expected to provide insights into the molecular mechanisms of TALL- 1/BCMA signaling and TALL-1/BCMA triggered biological effects. The genes and their protein products identified in this study may be used as molecular targets for drug development against certain immune-deficient and autoimmune diseases.
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