MURINE MODELS OF THE WISKOTT ALDRICH SYNDROME

Wiskott-Aldrich综合征（WAS）是一种血液系统疾病， 其特征在于T细胞和B细胞免疫缺陷、湿疹， 血小板减少症 有缺陷的蛋白质（WASP）被认为是发挥作用， 在造血细胞的复杂信号通路中起关键作用， 涉及细胞表面信号和细胞骨架的协调 结构变化。 最近，我们已经破坏了小鼠中的WAS基因， 胚胎干（ES）细胞，并使用RAG 2缺陷胚泡 互补系统，以显示WASP缺陷型小鼠淋巴细胞具有 与WAS患者中的缺陷非常相似的增殖缺陷。 此外，我们还鉴定了几种细胞信号分子， 包括Cdc 42，它们与WASP相互作用。 最后，我们确定了 第二个WASP家族成员（N-WASP.这 该项目旨在建立这些研究，以建立一个小鼠模型， 的WAS，并进一步阐明WASP和WASP相关的功能， proteins. 我们的第一个目标是描述功能的缺陷， WASP和WASP相关蛋白。 我们的首要目标是描述缺陷的特征 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学评估N-WASP功能 比较接近。 第三个目标是雇佣人类WASP- 血小板缺陷和WASP缺陷小鼠研究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的功能结构域通过遗传互补 接近。 这些研究应该提供进一步的洞察力， 与WAS相关的发病机制，同时提供更一般的见解 WASP家族蛋白在细胞内信号通路中的作用 控制着细胞骨架重组

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.