Regulation of cytoskeletal activation in NK cells

描述（由申请人提供）：自然杀伤细胞（NK）是淋巴细胞，在防御疾病和维持健康方面具有重要功能。NK细胞的一些特性使其成为研究细胞内信号传导和细胞骨架生物学及其与免疫功能关系的良好模型。其中包括一组特性良好的抑制性受体，它们通过磷酸酶活性和特异性激活受体诱导的激酶途径下调细胞活性，与其他淋巴细胞有显著区别。候选人提出的初步数据表明，细胞骨架调节过程对NK细胞功能很重要。对编码WAS蛋白（WASp）基因突变的Wiskott-Aldrich综合征（WAS）患者的研究已被证明在这方面特别有用。研究发现，促进肌动蛋白网络分支的WASp与丝状肌动蛋白一起聚集在NK细胞激活免疫突触处，肌动蛋白重排和NK细胞功能需要完整的WASp功能。在WAS患者的NK细胞中发现的缺陷很可能有助于他们的临床表现。本申请中提出的研究将验证NK细胞中细胞骨架活化的调节是诱导和抑制NK细胞功能的关键过程这一假设。特别是，研究者提出：1)NK细胞中某些关键的细胞内信号事件将激活受体连接与细胞骨架激活和功能联系起来；2) NK细胞中肌动蛋白骨架与微管网络之间存在重要的相互关系；3)细胞骨架是NK细胞抑制受体介导的NK细胞功能抑制的靶点。这些研究有可能揭示细胞骨架调节的新途径，并解决导致免疫细胞功能的细胞骨架事件的相互依赖性。候选人在小鼠细胞免疫学和体内免疫反应方面有广泛的背景。通过这个项目，他将发展生物化学方面的技能，并精通细胞内信号的研究。此外，候选人将大大扩展他的分子生物学能力，并继续熟练掌握人类细胞免疫学。申请人将在免疫缺陷以及与免疫功能相关的细胞骨架方面的权威Raif Geha博士和自然杀伤细胞生物学和生物化学方面的专家Jack Strominger博士的指导下进行这些工作。最终，候选人计划利用他作为儿科免疫学家的职位，更好地了解NK细胞的功能和NK细胞在维持人类健康中的作用。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are lymphocytes that serve important functions in defense against disease and maintenance of health. Several characteristics of NK cells make them an excellent model to pursue studies in intracellular signaling and cytoskeletal biology and their relation to immune function. These include a well characterized set of inhibitory receptors that downregulate cell activities through phosphatase activity and specific activating receptor-induced kinase pathways having notable distinctions from those in other lymphocytes. The candidate presents preliminary data suggesting that cytoskeletal regulatory processes are important to NK cell function. Studies of patients with Wiskott-Aldrich syndrome (WAS) having a mutation in the gene encoding the WAS protein (WASp) have proven particularly useful in this regard. WASp, which promotes the branching of actin networks, was found to accumulate with filamentous actin at NK cell activating immunologic synapses and intact WASp function was required for actin rearrangement and NK cell function. It is likely that the deficits found in NK cells of patients with WAS contribute to their clinical presentation. The studies proposed in this application will test the hypothesis that the regulation of cytoskeletal activation in NK cells is a critical process for the induction and inhibition of NK cell function. In particular, the investigator proposes: 1) certain key intracellular signaling events link activating receptor ligation to cytoskeletal activation and function in NK cells; 2) there is a critical interrelationship between the actin cytoskeleton and microtubular network in NK cells; and 3) the cytoskeleton is a target of NK cell inhibitory receptor-mediated inhibition of NK cell function. These studies hold the potential to uncover novel pathways of cytoskeletal regulation and address the interdependence of cytoskeletal events leading to immune cell function. The candidate has an extensive background in mouse cellular immunology and in vivo immune responses. By undertaking this project he will develop skills in biochemistry and become proficient in the investigation of intracellular signaling. Furthermore the candidate will greatly expand his molecular biology capabilities and continue to gain proficiency in human cellular immunology. The applicant will be mentored in these efforts by Dr. Raif Geha, an authority on immunodeficiency as well as the cytoskeleton as it relates to immune function, and Dr. Jack Strominger an expert in natural killer cell biology and biochemistry. Ultimately, the candidate plans to use his position as a pediatric immunologist to better understand NK cell function and the role NK cells play in maintenance of human health.