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

项目摘要 目前我正在使用化学遗传学、siRNA筛选和质谱学- 以蛋白质组学为基础，探索Wnt/-catenin信号通路。使用这些 我们发现Tec激酶是Wnt/-catenin的负调控因子的技术 发信号。因为Tec激酶BTK的突变是X-连锁的原因 无丙种球蛋白血症，我们试图证实我们最初在B细胞上的发现。 我们发现Tec激酶也负向调节B细胞中的Wnt/-catenin信号 培养中的细胞。这项工作使我产生了这样的假设，即技术和技术的相互作用 激酶和Wnt信号将在体内的造血过程中发挥重要作用。我 我正在申请独立之路奖，以延长我的 博士后培训，这样我就可以了解疾病的动物模型和 造血术和获取如何解剖和收集小鼠的实用知识 骨髓，如何进行小鼠骨髓移植实验 以及如何用流式细胞仪分析这些实验。中概述的 为了验证我的假设，我将使用所有这些方法。作为一种 独立调查员我计划利用我在交叉口的独特地位 蛋白质组学与造血信号分子机制的探讨 细胞分化中的转导。这个方向不仅能让我 充分利用我到目前为止的培训，这将使我能够进入一个具有 重要的临床意义，如脐带血移植，骨髓 移植和癌症治疗。

Project Abstract 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.