THE ROLE OF MXBP, A TRANSCRIPTION FACTOR, IN AUTOIMMUNE

我对分子生物学产生了兴趣，我在几个 实验室，我曾在那里研究转录的生物化学， 地中海贫血的分子遗传学和分子内分泌学。这些 作为一名科学家，经历塑造了我的思维，并提供了一种 理解基础科学进展应用于 临床医学。在我的内科实习期间，我成为了 对风湿病的发病机制感兴趣。建议数 项目将允许我应用最先进的技术和方法 以揭开免疫不足的分子机制 自身免疫性疾病中的激活和滑膜增殖。 B和T淋巴细胞的激活及其伴随的类的诱导 主要组织相容性(MHC)和白介素2(IL-2)基因 自身免疫性的显著特征。滑膜II类分子的异常表达 在类风湿性关节炎中发现。我们已经克隆了 并鉴定了一种与X结合的转录因子mXBP。 小鼠A-αII类MHC基因中的盒转录元件。MXBP 与原癌基因相互作用并改变其DNA结合特性 在IL-2基因诱导和表达中起作用的产物Fos和Jun 淋巴细胞活化。首先，我们将描述mXBP在 过表达mXBP的II类基因，显性阴性 MXBP的突变体，在淋巴样细胞中，并用已知的刺激因子 监管II类。我们将使用类似的方法来检查 MXBP-Jun相互作用对IL-2基因表达的影响。要扩展这一分析 为了研究淋巴细胞的激活，我们将使转基因小鼠 在淋巴细胞中过表达mXBP(或显性负性突变体)。我们预计 这些小鼠具有免疫缺陷或高反应性/自身免疫 表型，并将表征它们的免疫反应。最后，我们会 分析mXBP在滑膜细胞II类和胶原酶基因中的作用 表情。这些研究可能揭示治疗的中心靶点。 干预自身免疫性疾病。 Glimcher博士的实验室拥有所需的所有技术方面的专业知识 项目并在以下方面做出了重大贡献 转录因子和了解II类调控。她 实验室坐落在一个大型医疗中心，拥有优秀的 免疫学、分子生物学和风湿学，并应提供 实现我勾勒出的目标的最佳环境。

I have developed my interest in molecular biology by working in several laboratories, where I have studied the biochemistry of transcription, molecular genetics of thalassemia, and molecular endocrinology. These experiences have molded my thinking as a scientist, and provided a framework for understanding the application of advances in basic science to clinical medicine. During my residency in Internal Medicine, I became interested in the pathogenesis of the rheumatic diseases. The proposed project will allow me to apply state of the art techniques and approaches of molecular biology to unravel molecular mechanisms which underly immune activation and synovial proliferation in autoimmune disease. Activation of B and T lymphocytes, and the accompanying induction of class II major histocompatibility (MHC) and interleukin-2 (IL-2) genes, are prominent features of autoimmunity. Aberrant synovial class II expression and proliferation are found in rheumatoid arthritis. We have cloned the cDNA and characterized a transcription factor, mXBP, which binds to the X box transcription element in the murine A-alpha class II MHC gene. mXBP interacts with and alters the DNA binding properties of proto-oncogene products Fos and Jun, which play a role in IL-2 gene induction and lymphocyte activation. Initially, we will characterize the role of mXBP in class II gene expression by overexpressing mXBP, and dominant negative mutants of mXBP, in lymphoid cells and stimulating with agents known to regulate class II. We will use similar approaches to examine the effect of the mXBP-Jun interaction on IL-2 gene expression. To extend this analysis to study lymphocyte activation, we will make transgenic mice which overexpress mXBP (or dominant negative mutants) in lymphocytes. We expect these mice to have an immunodeficient or hyper-reactive/autoimmune phenotype, and will characterize their immune responses. Finally, we will analyze the role of mXBP in synoviocyte class II and collagenase gene expression. These studies may reveal a central target for therapeutic intervention in autoimmune disease. Dr. Glimcher's laboratory has expertise in all techniques needed for this project and has made significant contributions in characterizing transcription factors and understanding class II regulation. Her laboratory is situated in a large medical center with excellent programs in immunology, molecular biology, and rheumatology, and should provide an optimal environment in which to achieve my outlined goals.