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 人类T细胞嗜淋巴病毒I型(HTLV-I)前病毒DNA可能作为 一种高度调控的病毒特异性RNA低水平表达模板 包括病毒反式激活剂TAX在内的蛋白质。首席调查员 (首席调查员)提出，这种表达模式是 一个高度特异的分化过程，它改变了水平，并可能 几种细胞转录因子的活性，它们激活和 保持较低水平的LTR活动，在 诱导涉及神经毒性作用的神经炎性过程 HTLV-I特异性细胞毒性T细胞与中枢神经系统细胞因子通路的失调 这会导致神经功能障碍，热带痉挛瘫痪(TSP)。这个 首席调查员将检查调节细胞和病毒因子 HTLV-I激活，新的重点是调节病毒表达 在CD34+祖细胞等造血细胞分化过程中 和单核细胞系的细胞，包括树突状细胞、巨噬细胞和 脑内小胶质细胞。这些研究将集中在细胞内的AP-1和Sp 转录因子家族及其在调节基础和超微结构中的作用 造血细胞分化过程中TAX介导的反式激活。这个 这一竞争性更新的目标将检查(1)HTLV-I的细胞调控 单核细胞分化过程中Sp和AP-1家族对LTR的激活 骨髓、外周血和脑中的谱系；(2)细胞内定位 HTLV-I税及其对LTR税收反应元件1(TRE-1)和TRE-2的影响 功能、Sp和AP-1的表达以及所选择的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 细胞系；(3)单核细胞原代细胞中税收介导的LTR激活 利用慢病毒载体和HTLV-I分子在骨髓、外周血和脑中的谱系 (4)紫杉醇与Sp和AP-1因子的分子相互作用。 选定的单核细胞启动子中的tre-1和顺式作用元件。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 神经炎症性疾病。

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.