REGULATION OF HTLV I LTR IN IMMUNE AND NERVOUS SYSTEMS

描述：研究表明，分化的树突状细胞和 外周血（PB）和淋巴结（LN）中活化的巨噬细胞含有 人T细胞嗜淋巴细胞病毒I型（HTLV-I）前病毒DNA，其可作为 用于病毒特异性RNA的高度调节的低水平表达的模板， 蛋白质包括病毒反式激活因子Tax。主要研究者 （主要研究者）提出，这种表达模式是 一种高度特异性的分化过程， 几种细胞转录因子的活性， 保持低水平的LTR活动，并在 诱导神经炎症过程，涉及神经毒性作用， HTLV-I特异性细胞毒性T细胞与CNS细胞因子通路的失调 导致神经系统疾病，热带痉挛性轻瘫（TSP）。的 主要研究者将检查细胞和病毒因子， HTLV-I激活与新的重点放在调节病毒的表达 在造血细胞如CD 34+祖细胞的分化过程中 和单核细胞谱系的细胞，包括树突细胞、巨噬细胞和 脑小胶质细胞本研究将集中在细胞AP-1和Sp 转录因子家族及其在调节基础和 造血细胞分化过程中Tax介导的反式激活。的 这一竞争性更新的目的将研究（1）HTLV-I的细胞调节 单核细胞分化过程中Sp和AP-1家族对LTR的激活 骨髓（BM），PB和脑中的谱系;（2）细胞内定位 HTLV-I税及其对LTR税收响应要素1（TRE-1）和TRE-2的影响 功能，Sp和AP-1表达，以及选择的Sp-和AP-1的功能 单核细胞分化过程中含有结合位点的单核细胞启动子 （3）单核细胞系原代细胞中Tax介导的LTR活化 利用慢病毒载体和HTLV-I分子在BM、PB和脑中的谱系 （4）Tax与Sp和AP-1因子的分子相互作用 TRE-1和顺式作用元件在选定的单核细胞启动子。这些研究 可能导致新的治疗方法来预防和/或治疗TSP或其他疾病。 神经炎性疾病

DESCRIPTION: Studies have suggested that differentiated dendritic cells and activated macrophages in peripheral blood (PB) and lymph nodes (LN) contain human T cell lymphotropic virus type I (HTLV-I) proviral DNA that may serve as a template for highly regulated low level expression of virus-specific RNA and proteins including the viral transactivator, Tax. The Principal Investigator (Principal Investigator) proposes that this expression pattern is the result of a highly specific differentiation process that alters the levels, and possibly the activity of several cellular transcription factors that activate and maintain a low level of LTR activity and is of central importance in the induction of a neuroinflammatory process that involves the neurotoxic action of HTLV-I-specific cytotoxic T cells and dysregulation of CNS cytokine pathways that leads to the neurologic disorder, tropical spastic paraparesis (TSP). The Principal Investigator will examine cellular and viral factors that regulate HTLV-I activation with new emphasis placed on regulation of viral expression during differentiation of hematopoietic cells such as CD34+ progenitor cells and cells of the monocytic lineage including dendritic cells, macrophages, and brain microglial cells. The studies will focus on the cellular AP-1 and Sp transcription factor families and their role in modulating basal and Tax-mediated transactivation during hematopoietic cell differentiation. The aims of this competing renewal will examine (1) cellular regulation of HTLV-I LTR activation by Sp and AP-1 families during differentiation of the monocytic lineage in bone marrow (BM), PB, and brain; (2) intracellular localization of HTLV-I Tax and its impact on LTR Tax responsive element 1 (TRE-1) and TRE-2 function, Sp and AP-1 expression, and the function of selected Sp- and Ap-1 binding site-containing monocytic promoters during differentiation in monocytic cell lines; (3) Tax-mediated LTR activation in primary cells of the monocytic lineage in BM, PB, and brain utilizing lentiviral vectors and HTLV-I molecular clones; and (4) molecular interaction of Tax with Sp and AP-1 factors with TRE-1 and cis-acting elements in selected monocytic promoters. These studies could lead to new therapeutic approaches to prevent and/or treat TSP or other neuroinflammatory diseases.