THE ROLE OF MXBP, A TRANSCRIPTION FACTOR, IN AUTOIMMUNE

我已经开发了我在分子生物学的兴趣，通过在几个 实验室，在那里我研究了转录的生物化学， 地中海贫血的分子遗传学和分子内分泌学。 这些 这些经历塑造了我作为一名科学家的思想，并提供了一个 理解基础科学进展应用于 临床医学 在我的内科住院期间，我成为了 对风湿性疾病的发病机理感兴趣。 拟议 该项目将使我能够应用最先进的技术和方法 来解开免疫系统的分子机制 活化和滑膜增殖的影响。 B和T淋巴细胞的活化，以及伴随的类 II主要组织相容性（MHC）和白细胞介素-2（IL-2）基因， 自身免疫的突出特点。 异常滑膜II类表达 和增殖在类风湿性关节炎中被发现。 我们克隆了 cDNA和特征的转录因子，mXBP，它结合到X 在鼠A-α II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 产物Fos和Jun，其在IL-2基因诱导中起作用， 淋巴细胞活化 首先，我们将描述mXBP在以下方面的作用： II类基因表达通过过表达mXBP，和显性阴性 mXBP的突变体，在淋巴细胞中，并用已知的试剂刺激， 调节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。 为了扩展这个分析， 为了研究淋巴细胞的活化，我们将制造转基因小鼠， 在淋巴细胞中过表达mXBP（或显性阴性突变体）。 我们预计 这些小鼠具有免疫缺陷或高反应性/自身免疫性 表型，并将表征其免疫反应。 最后我们将 分析mXBP在II类滑膜细胞和胶原酶基因中的作用 表情 这些研究可能揭示了治疗的中心目标 自身免疫性疾病的干预。 博士格里姆彻的实验室拥有这方面所需的所有技术的专业知识 项目，并作出了重大贡献， 转录因子和理解II类调控。 她 实验室位于一个大型医疗中心，在 免疫学、分子生物学和流变学，并应提供一个 最佳的环境来实现我的目标。

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.