IMMUNE RESPONSE TO NUCLEAR CONSTITUENTS IN SLE

Ku蛋白最初是作为一种自身抗原被发现的 多发性肌炎-硬皮病重叠综合征患者的血清。它 由70 kDa和80 kDa亚基组成，结合双链末端 搁浅的DNA。目前的建议寻求的生物功能 Ku蛋白通过努力确定与其相关的其他蛋白 互动。我们的初步研究表明，其中一个例子是 酶DNA依赖蛋白激酶(DNA-PK)。这种酶使磷酸化 几种转录因子，包括羧基末端结构域 RNA聚合酶的大亚基II。这些研究将寻求 证明Ku和DNA-PK组装成大分子结构 他们将确定是否有其他蛋白质参与这一过程 很复杂。目前正在努力定义DNA的形式，这些形式与 Ku杂二聚体将继续存在。最后，将进行研究 以确定是否存在自身抗体的协调表达 对患者Ku蛋白-DNA-PK复合体各组分的影响 患有系统性红斑狼疮、硬皮病和多发性肌炎。这些研究将 检验Ku蛋白与350 kDa形成复合体的假说 DNA-PK的催化多肽并将后者引导到适当的 DNA上特定转录因子的磷酸化位点 必填项。它还将检验一个假设，即在结缔组织中 疾病选定的大分子结构是自身免疫的靶点 应答的结果是，自身抗体家族被定向 针对目标结构的不同组件。这些研究 将为研究如何选择“自我”奠定基础 结构与免疫系统接触，要么是通过 从细胞中挤出，或由于组装、运输或 多肽片段插入MHC的结果是周转率 分子，并在细胞表面表达，呈现给免疫 系统。

The Ku protein was initially discovered as an autoantigen recognized by sera from patients with polymyositis-scleroderma overlap syndrome. It consists of 70 kDa and 80 kDa subunits and it binds ends of double stranded DNA. The present proposal seeks the biological function of the Ku protein through an effort to identify other proteins with which it interacts. Our preliminary studies indicate that one example is the enzyme DNA-dependent protein kinase (DNA-PK). this enzyme phosphorylates several transcription factors including the carboxyl terminal domain of the large subunit of RNA polymerase II. these studies will seek to demonstrate that Ku and DNA-PK assemble into a macromolecular structure on DNA and they will determine if other proteins participate in this complex. Ongoing efforts to define the forms of DNA which are bound by the Ku heterodimer will be continued. finally, studies will be carried out to determine if there is a coordinated expression of autoantibodies to the various components of the Ku protein-DNA-PK complex in patients with systemic lupus, scleroderma, and polymyositis. These studies will test the hypothesis that Ku protein forms a complex with the 350 kDa catalytic polypeptide of DNA-PK and directs the latter to appropriate sites on DNA where phosphorylation of specific transcription factors is required. It will also test the hypothesis that in the connective tissue diseases selected macromolecular structures are targeted for autoimmune responses with the result that families of autoantibodies are directed against different components of the targeted structure. These studies will lay the foundation for studies which can address how selected "self" structures come into contact with the immune system, either through extrusion from cells or from disruption of assembly, transport, or turnover with the outcome that peptide fragments are inserted into MHC molecules and expressed on cell surfaces for presentation to the immune system.