ROLE OF SYK PROTEIN TYROSINE KINASE IN IMMUNE FUNCTION

正常免疫反应的产生需要免疫系统内多个细胞成分的协调激活和功能。这些细胞成分中的一个或多个的缺陷可能导致从免疫缺陷到自身免疫的各种疾病。大多数免疫细胞的正常功能依赖于多个蛋白酪氨酸激酶(PTK)家族的适当激活。一个这样的家族，Syk家族的PTKs，已被证明在广泛的造血源细胞中发挥关键作用，并与多种受体的功能有关。虽然关于Syk PTK在免疫细胞发育和功能中的生物化学和发育作用已经了解很多，但关于Syk如何调节细胞激活和生物结果却知之甚少。这个PPG应用程序将利用多学科方法分析Syk调节B细胞和自然杀伤细胞功能的机制，开发项目1将实时分析Syk中一个新的调节域在B细胞抗原受体激活中的功能和Syk功能的动态。项目2将确定B细胞发育过程中Syk对BCR前功能的结构要求，并将询问BCR信号能力的变化是否会影响BCR谱系的选择，即表达具有酶活性增加或降低的Syk酶。项目3将剖析这个PTK家族在自然杀伤细胞功能和发育中的作用。来自每个项目的见解将加强其他项目利用的实验方法。这种多学科的方法不仅将提供对Syk如何调节免疫细胞功能的更深入的了解，也可能为PTK如何调节生物过程提供洞察力。这些见解反过来可能提供机制信息，为治疗自身免疫性疾病和移植排斥反应的药物设计提供更合理的治疗方法基础。

The generation of a normal immune responses requires the coordinate activation and function of multiple cellular components within the immune system. Deficiencies in one or more of these cellular components can result in diseases ranging from immunodeficiency to autoimmunity. Appropriate function of most immune cells is dependent on the appropriate activation of multiple families of protein tyrosine kinases (PTKs). One such family, the Syk-family of PTKs, has been demonstrated to play a critical role in a wide number of hematopoietic derived cells and has been implicated in the function of a variety of receptors. While much has been learned about the biochemistry and developmental role of the Syk PTK in immune cell development and function, little is known about how Syk regulates cellular activation and biologic outcome. This PPG application will utilize a multi-disciplinary approach to analyze the mechanisms by which Syk regulates B cell and natural killer cell function and development Project 1 will analyze the function of a novel regulatory domain within Syk in B cell antigen receptor activation and dynamics of Syk function in real time. Project 2 will determine the structural requirements within Syk for pre-BCR function during B cell development and will also ask whether alterations in the signaling capacity of the BCR, by expressing Syk enzymes with increased or decreased enzymatic activities, can affect the selection of the BCR repertoire. Project 3 will dissect the function of this family of PTKs in natural killer cell function and development. Insights from each project will enhance the experimental approaches utilized by the other projects. This multi-disciplinary approach will not only provide a more in-depth understanding of how Syk regulates immune cell function, but may also provide insights into how PTKs regulate biological processes. These insights, in turn, may provide mechanistic information that may serve as the basis for more rational therapeutic approaches for drug design for autoimmune diseases and transplantation rejection.