MURINE MODELS OF THE WISKOTT ALDRICH SYNDROME

Wiskott-Aldrich综合征是一种血液系统疾病。 以T和B细胞免疫缺陷、湿疹和 血小板减少症。缺陷蛋白(WASP)被认为是一种 在造血细胞中复杂的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 结构性变化。最近，我们打乱了小鼠的was基因。 胚胎干细胞，并使用RAG2缺陷的囊胚 互补系统显示WASP缺陷的小鼠淋巴细胞有 与IS患者的缺陷非常相似的增殖缺陷。 此外，我们还鉴定了几个细胞信号分子， 包括与WASP相互作用的CDC42。最后，我们确定了 第二个WASP-家族成员的人和鼠的同源物(N-WASP。这 该项目试图在这些研究的基础上建立一种小鼠模型 并进一步阐明了WASP和WASP相关的功能 蛋白质。我们的第一个目标是描述功能的缺陷 黄蜂和黄蜂相关蛋白。我们的首要目标是确定缺陷的特征 对WASP缺陷小鼠的免疫系统的影响。我们的第二个目标是 用基因靶向突变和遗传学方法评价N-WASP的功能 完成的方式越来越近。第三个目标是使用人类WASP- WASP对血小板缺陷小鼠和WASP缺陷小鼠的作用研究 血小板的产生和功能。我们的最终目标是澄清 WASP和N-WASP功能结构域的遗传互补 接近了。这些研究应该会进一步深入了解 与AS相关的机制，同时提供更全面的见解 WASP家族蛋白在细胞内信号通路中的作用 它控制着细胞骨架的重组。

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.