MURINE MODELS OF THE WISKOTT ALDRICH SYNDROME

威斯科特-奥尔德里奇综合征 (WAS) 是一种血液系统疾病 以 T 细胞和 B 细胞免疫缺陷、湿疹和 血小板减少症。 有缺陷的蛋白质（WASP）被认为发挥着 在造血细胞复杂的信号通路中发挥关键作用 涉及细胞表面信号和细胞骨架的协调 结构性变化。 最近，我们破坏了小鼠的 WAS 基因 胚胎干 (ES) 细胞并使用 RAG2 缺陷型囊胚 互补系统表明 WASP 缺陷的小鼠淋巴细胞 增殖缺陷与 WAS 患者的缺陷非常相似。 此外，我们还鉴定了几种细胞信号分子， 包括与 WASP 交互的 Cdc42。 最后，我们确定了 第二个 WASP 家族成员 (N-WASP) 的人类和鼠类同源物。 该项目旨在以这些研究为基础，建立一个小鼠模型 WAS并进一步阐明WASP的功能以及WASP相关 蛋白质。 我们的首要目标是表征功能的缺陷 WASP 和 WASP 相关蛋白。 我们的首要目标是表征缺陷 WASP 缺陷小鼠的免疫系统。 我们的第二个目标是 通过基因靶向突变和遗传评估 N-WASP 功能 互补方法。 第三个目标是雇用人类 WASP- 缺陷血小板和 WASP 缺陷小鼠，以研究 WASP 在 血小板的产生和功能。 我们的最终目标是阐明 WASP 和 N-WASP 的功能域通过遗传互补 接近。 这些研究应该提供进一步的见解 与 WAS 相关的发病机制，同时提供更一般的见解 研究 WASP 家族蛋白在细胞内信号通路中的作用 控制细胞骨架重组。

The Wiskott-Aldrich syndrome (WAS) is a hematological disorder characterized by a T-and B-cell immunodeficiency, eczema, and thrombocytopenia. The defective protein (WASP) is thought to play a critical role in a complex signaling pathway in hematopoietic cells that involves the coordination of cell surface signals and cytoskeletal structural changes. Recently, we have disrupted the WAS gene in murine embryonic stem (ES) cells and used the RAG2-deficient blastocyst complementation system to show that WASP-deficient murine lymphocytes have proliferation defects that closely resemble the defects in WAS patients. In addition, we have identified several cellular signaling molecules, including Cdc42, that interact with WASP. Finally, we have identified th human and murine homologues of the second WASP-family member (N-WASP. This project seeks to build on these studies to establish a murine model for the WAS and to further elucidate the function of WASP and WASP-related proteins. Our first aim is to characterize defects of the function of WASP and WASP-related proteins. Our first aim is to characterize defects of the immune system in WASP-deficient mice. Our second goal is to evaluate N-WASP function by gene targeted mutational and genetic comlementation approaches. The third goal is to employ human WASP- deficient platelets and WASP-deficient mice to study the role of WASP in platelet production and function. Our final goal is to elucidate functional domains of WASP and N-WASP by genetic complementation approaches. These studies should provide further insight into the pathogenesis associated with WAS while providing more general insights into the role of WASP-family proteins in intracellular signaling pathways that control cytoskeletal reorganization.