Currently I am using chemical genetics, siRNA screens and mass spectrometry- based proteomics to probe the Wnt/ -catenin signaling pathway. Using these techniques we identified Tec kinases as negative regulators of Wnt/ -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/ -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/ -catenin related symptoms such as colorectal carcinoma, and 2) using Tec kinase inhibition to increase the efficacy of human cord blood in clinical engraftment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL103768-04
Application #
8532963
Study Section
Special Emphasis Panel (NSS)
Program Officer
Welniak, Lisbeth A
Project Start
2010-08-14
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$232,883
Indirect Cost
$112,840
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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Fleming, Britannia M; Yelin, Ronit; James, Richard G et al. (2013) A role for Vg1/Nodal signaling in specification of the intermediate mesoderm. Development 140:1819-29
Moore, Kaitlyn E; Carlson, Scott M; Camp, Nathan D et al. (2013) A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol Cell 50:444-56