IMMUNE RESPONSE TO NUCLEAR CONSTITUENTS IN SLE

Ku蛋白最初被发现是一种自身抗原， 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，它结合双链末端， 链dna 目前的建议寻求的生物功能， Ku蛋白通过努力鉴定其他蛋白质， 互动。 我们的初步研究表明，一个例子是， DNA依赖性蛋白激酶（DNA-PK）。 这种酶磷酸化 几种转录因子，包括 RNA聚合酶II的大亚基。 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其中 复杂. 目前正在努力确定DNA的形式， Ku异二聚体将继续进行。 最后，进行研究， 以确定是否存在自身抗体的协调表达 患者体内Ku蛋白-DNA-PK复合物的各种成分 系统性狼疮硬皮病和多发性肌炎 这些研究将 测试Ku蛋白与350 kDa的蛋白质形成复合物的假设， DNA-PK的催化多肽，并将后者引导至适当的 DNA上的位点，其中特定转录因子的磷酸化被 必需的. 它还将检验在结缔组织中 疾病选定的大分子结构是针对自身免疫性 结果，自身抗体家族被定向 针对目标结构的不同组成部分。 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，或者通过 从细胞中挤出或从组装、运输或 结果是肽片段插入MHC 分子并在细胞表面表达以呈递给免疫系统 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.