ROLE OF LIPOPOLYSACCHARIDE IN CONNECTIVE TISSUE DISEASE

在我的内科和病理学综合实习期间，我 对风湿病的发病机制产生了兴趣。 在风湿科做了一年的临床研究员后，我进入了 劳里·格里姆彻博士的实验室。我的目的是学习基本的工具 分子生物学的研究。最终，我计划将这些工具与我的 病理学知识，接近对风湿病的认识 疾病。拟议的项目将使我能够掌握 田野，疾病。拟议的项目将使我能够掌握 这一领域的技术，同时也解决了关键问题 关于组织破坏的触发和放大 结缔组织病。 第二类主要组织相容性复合体蛋白的异常表达 是自身免疫力的一个显著特征。这样的表达出现在 滑膜、近端小管、甲状腺、胰岛和其他组织 在各种自身免疫状态下。尽管目前还不知道 II类异常表达是初始事件还是继发性事件 增强自身免疫过程的现象，初步证据 这表明在一些疾病州，II类病毒水平的增加 在组织破坏之前。 已知脂多糖(LPS)可诱导血管内皮细胞第II类分子表达 细胞类型和自身免疫状态的数量。我们已经确定了一个 小鼠脾细胞核提取液中的核因子-内毒素。 核因子-内毒素在内毒素刺激下可被诱导，并与两个序列结合 在小鼠AalphaII类基因的上游调控区。 首先，我们将集中研究这种蛋白质的特性，并 它的结合部位。随后，我们将获得编码以下基因的cDNA克隆 该蛋白来自lambda(Gt11)表达文库。抗该病毒的抗体 然后就可以制备蛋白质了。一旦获得这些试剂，就会使用 研究核因子-内毒素在诱导动物产生II类分子中的作用 葡萄膜炎模型。最终目标是选择性地操纵核因子-内毒素 II类异常表达和后续组织的活性 破坏是可以避免的。 Glimcher博士的实验室已经拥有所需技术的专业知识 ，最近已经成功克隆了几个 结合DRAlpha和AAlpha基因调控区的蛋白质。这 实验室将是实现我的目标的绝佳环境 勾勒的目标。

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.