ROLE OF LIPOPOLYSACCHARIDE IN CONNECTIVE TISSUE DISEASE

在我的内科和病理学实习期间，我 对风湿性疾病的发病机理产生了兴趣。 在做了一年的流变学临床研究员后，我进入了 劳里·格利姆彻博士的实验室。我的目的是学习基本工具 分子生物学。最终，我计划将这些联合收割机与我的 病理学知识，了解风湿性关节炎 疾病建议的项目将使我掌握的技术， 场，疾病。建议的项目将使我掌握 这一领域的技术，同时也解决关键问题， 关于组织破坏的触发和放大， 结缔组织病 II类主要组织相容性复合体蛋白的异常表达 是自身免疫的一个显著特征。这种表达方式存在于 滑膜、近端小管、甲状腺、胰岛和其他组织 处于各种自身免疫状态虽然不知道是否 异常II类表达是初始事件或继发事件， 增强自身免疫过程的现象，初步证据 表明，在某些疾病状态下，II级水平的增加， 在组织破坏之前。 已知脂多糖（LPS）在哺乳动物中诱导II类表达。 细胞类型的数量，以及自身免疫状态。我们已经确定了一 核因子，NF-LPS，从小鼠脾脏制备的核提取物。 NF-LPS在用LPS刺激时是可诱导的，并结合两个序列 在小鼠A α II类基因的上游调控区。 首先，我们将专注于这种蛋白质的表征， 其结合位点。随后，我们将获得一个cDNA克隆， 该蛋白来自λ（GT 11）表达文库。抗体与 然后可以制备蛋白质。一旦获得，这些试剂将用于 研究NF-LPS在动物中诱导II类中的作用 葡萄膜炎模型。最终的目标是选择性地操纵NF-LPS 活性使得异常的II类表达和随后的组织 破坏被阻止了。 格里姆彻博士的实验室已经具备了所需技术的专业知识 最近成功地克隆了几个 与DR α和A α基因调控区结合的蛋白质。这 实验室将是一个很好的环境，实现我的 概述的目标。

During my combined residency in Internal Medicine and Pathology, I developed an interest in the pathogenesis of the rheumatic diseases. After one year as a clinical fellow in Rheumatology, I entered the laboratory of Dr. Laurie Glimcher. My intent was to learn the basic tools of molecular biology. Ultimately, I plan to combine these tools with my knowledge of pathology, to approach an understanding of rheumatic disease. The proposed project will allow me to master the techniques of the field, disease. The proposed project will allow me to master the techniques of this field, while also addressing critical questions regarding the triggering and amplification of tissue destruction in connective tissue disease. Aberrant expression of class II major histocompatibility complex proteins is a prominent feature in autoimmunity. Such expression is present in synovium, proximal tubules, thyroid, pancreatic islets, and other tissues in a variety of autoimmune states. Although it is not known whether aberrant class II expression is the initial event or a secondary phenomenon potentiating the autoimmune process, preliminary evidence suggests that in some disease states, increased levels of class II precede tissue destruction. Lipopolysaccharide (LPS) is known to induce class II expression in a number of cell types, and in autoimmune states. We have identified a nuclear factor, NF-LPS, in nuclear extracts prepared from mouse spleen. NF-LPS is inducible upon stimulation with LPS and binds to two sequences in the upstream regulatory region of the mouse Aalpha class II gene. Initially we will concentrate on the characterization of this protein and its binding sites. Subsequently we will obtain a cDNA clone coding for this protein from a lambda(gt11) expression library. Antibody to the protein can then be prepared. Once obtained, these reagents will be used to study the role of NF-LPS in the induction of class II in an animal model of uveitis. The eventual goal is to selectively manipulate NF-LPS activity such that aberrant class II expression and subsequent tissue destruction is prevented. Dr Glimcher's laboratory already has expertise in the techniques needed for this project, and has recently been successful in cloning several proteins binding to regulatory regions of DRalpha and Aalpha genes. This laboratory will be an excellent environment in which to achieve my outlined goals.