In vivo role of BTK-mediated inhibition of Wnt/b-catenin signaling during hematop

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DESCRIPTION (provided by applicant): Currently I am using chemical genetics, siRNA screens and mass spectrometry- based proteomics to probe the Wnt/b-catenin signaling pathway. Using these techniques we identified Tec kinases as negative regulators of Wnt/b-catenin signaling. Because mutations in the Tec kinase BTK are responsible for X-linked agammaglobulinemia, we sought to corroborate our original findings in B cells. We found that Tec kinases also negatively regulate Wnt/b-catenin signaling in B cells in culture. This work has led me to the hypothesis that the interplay of Tec kinases and Wnt signaling will have a significant role in hematopoiesis in vivo. I am applying for the Pathway to Independence Award in order to extend my postdoctoral training so that I can learn about animal models of disease and hematopoiesis and gain practical knowledge of how to dissect mice and collect bone marrow, how to perform murine bone marrow transplantation experiments and how to analyze these experiments by flow cytometry. As outlined in the proposal, I will use all of these methods in order to test my hypothesis. As an independent investigator I plan to exploit my unique position at the intersection of proteomics and hematopoiesis to explore the molecular mechanisms of signal transduction in cellular differentiation. Not only would this direction allow me to fully utilize my training to date, it would allow me to enter a field that has important clinical implications, such as cord blood engraftment, bone marrow transplant and cancer treatments. PUBLIC HEALTH RELEVANCE: In addition to testing an interesting basic science hypothesis, the results of this proposal are likely to be relevant to the mission of the NHLBI in two areas: 1) informing clinicians treating patients diagnosed with X-linked agammaglobulinemia to focus attention to Wnt/b-catenin related symptoms such as colorectal carcinoma, and 2) using Tec kinase inhibition to increase the efficacy of human cord blood in clinical engraftment.