HTLV-1 & Cellular Factors in Neuroinflammatory Disease

HTLV-1

基本信息

批准号：
9287115
负责人：
Pooja Jain
金额：
$ 2.95万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9287115
关键词：
Accounting Adult T-Cell Leukemia/Lymphoma Antigen-Presenting Cells Automobile Driving Biochemical Bone Marrow CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chromatin Chromatin Remodeling Factor Clone Cells Code Communities Complex DNA DNA-Protein Interaction Development Disease EP300 gene Etiology Family Family member Gene Expression Gene Expression Regulation Genetic Transcription Genome HIV-1 Histones Human T-lymphotropic virus 1 Individual Investigation Life Cycle Stages Link Long Terminal Repeats Luc Gene Mediating Messenger RNA MicroRNAs Molecular Neuraxis Neuropathogenesis Nucleosomes PCAF gene Pathogenesis Pathway interactions Patients Pattern Plasmids Play Population Primary Infection Protein Biosynthesis Proteins Proviruses Regulation Reporter Reporting Role Spinal Cord Diseases Staging Stem cells T-Lymphocyte Target Populations Taxes Testing Therapeutic Intervention Transcription Repressor/Corepressor Tropical Spastic Paraparesis Viral Viral Genes Viral Genome Viral Proteins Virus Virus Diseases Virus Latency cell type chromatin remodeling cohort comparative histone acetyltransferase in vivo innovation insight macrophage molecular marker monocyte nervous system disorder neuroinflammation novel novel therapeutics prevent progenitor promoter reactivation from latency research study response targeted treatment tax Gene Products tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus preferentially targets CD4+ T cels, but also infects other secondary cell types such as CD8+ T cells, bone marrow progenitor cells, cells of the monocyte-macrophage lineage, and resident CNS cell populations. Previous studies from us and others have suggested that virus-induced alterations in these cell compartments play important roles in the genesis of the progressive neurological disorder HAM/TSP. However, little information exists concerning the molecular mechanisms of HTLV-1 promoter (long terminal repeat or LTR) regulation in these cells. Moreover, nearly all studies highlighting the importance of the cellular transcription factors in HTLV-1 Tax-mediated LTR activation and the ability of Tax protein to interact with these factors independently have been performed using transiently transfected viral reporter plasmids or in cell lines that do not represent the primary target for HTLV-1 in vivo. Studies performed with HIV-1 have indicated that the integrated provirus differs from a transfected viral plasmid both physically and in the requirement for certain cellular factors, especially those belonging to the chromatin remodeling histone acetyltransferase (HAT) family. Hence, to better understand HTLV-1 gene regulation and the complex interplay with the integrated provirus, we previously characterized a number of stable clones of CD4+ T-cell (Jurkat), monocyte (U-937), and progenitor (TF-1) cell lines carrying integrated copies of the HTLV-1 LTR driving luciferase gene expression. Preliminary investigations using these clones have highlighted novel interactions between the Tax protein and host microRNAs involved in regulating chromatin remodeling leading to the proposed studies. Our results are consistent with a novel hypothesis that Tax can modulate the cellular miRNA machinery in a cell-type specific manner involving chromatin remodeling effecting viral gene expression controled by the HTLV-1 LTR. The Specific Aims to validate this concept and to test our hypothesis are to (1) Investigate the mechanism of Tax- mediated DNA-protein interactions in the context of chromatin in primary and secondary target cell populations during the course of viral disease, (2) Define HTLV-1 Tax-modulated host miRNA expression linked to chromatin remodeling in primary and secondary cell populations targeted by HTLV-1, and (3) Validate role of Tax-miRNA-chromatin interactions in HTLV-1 disease in patient cohort(s). The proposed studies ofer the potential to answer basic key questions related to HTLV-1 pathogenesis and will provide novel insight into why many CD4+ T cells in infected individuals containing HTLV-1 proviral sequences do not express viral proteins. In addition, these studies will provide a comparative account of molecular mechanism(s) related to HTLV-1 gene regulation in T cells versus bone marrow progenitor cells and cells of the monocyte-macrophage lineage, which are critical cellular components involved in retroviral neuropathogenesis.

描述（由申请人提供）：人类 T 细胞白血病病毒 1 型 (HTLV-1) 是成人 T 细胞白血病 (ATL) 和神经系统疾病、HTLV-1 相关脊髓病/热带痉挛性截瘫 (HAM) 的病原体/TSP）。该病毒优先针对 CD4+ T 细胞，但也会感染其他次级细胞类型，例如 CD8+ T 细胞、骨髓祖细胞、单核细胞-巨噬细胞谱系的细胞和常驻 CNS 细胞群。我们和其他人之前的研究表明，病毒诱导的这些细胞区室的改变在进行性神经系统疾病 HAM/TSP 的发生中发挥着重要作用。然而，关于这些细胞中 HTLV-1 启动子（长末端重复或 LTR）调节的分子机制的信息很少。此外，几乎所有强调细胞转录因子在 HTLV-1 Tax 介导的 LTR 激活中的重要性以及 Tax 蛋白与这些因子独立相互作用的能力的研究都是使用瞬时转染的病毒报告质粒或在不具有瞬时转染的病毒报告质粒的细胞系中进行的。代表 HTLV-1 体内的主要靶标。对 HIV-1 进行的研究表明，整合的原病毒与转染的病毒质粒在物理上和对某些细胞因子的需求方面有所不同，特别是那些属于染色质重塑组蛋白乙酰转移酶 (HAT) 家族的细胞因子。因此，为了更好地了解 HTLV-1 基因调控以及与整合原病毒的复杂相互作用，我们之前对 CD4+ T 细胞 (Jurkat)、单核细胞 (U-937) 和祖细胞 (TF-1) 的许多稳定克隆进行了表征携带驱动荧光素酶基因表达的 HTLV-1 LTR 整合副本的细胞系。使用这些克隆进行的初步研究强调了 Tax 蛋白和参与调节染色质重塑的宿主 microRNA 之间的新相互作用，从而导致了拟议的研究。我们的结果与一个新的假设相一致，即 Tax 可以以细胞类型特异性方式调节细胞 miRNA 机制，涉及染色质重塑，影响由 HTLV-1 LTR 控制的病毒基因表达。验证这一概念并检验我们的假设的具体目标是 (1) 研究病毒性疾病过程中初级和次级靶细胞群染色质背景下 Tax 介导的 DNA-蛋白质相互作用的机制，(2)定义与 HTLV-1 靶向的原代和次生细胞群中染色质重塑相关的 HTLV-1 Tax 调节的宿主 miRNA 表达，以及 (3) 验证 Tax-miRNA-染色质相互作用在患者队列中的 HTLV-1 疾病。拟议的研究有可能回答与 HTLV-1 发病机制相关的基本关键问题，并将提供新的见解，解释为什么感染个体中含有 HTLV-1 前病毒序列的许多 CD4+ T 细胞不表达病毒蛋白。此外，这些研究将提供 T 细胞与骨髓祖细胞和单核巨噬细胞谱系细胞中 HTLV-1 基因调控相关的分子机制的比较说明，单核细胞-巨噬细胞谱系是参与逆转录病毒神经发病机制的关键细胞成分。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection.

鼠FLT3配体衍生的树突状细胞介导的早期免疫反应对于控制无细胞人T细胞白血病病毒1型感染至关重要。

DOI：
10.4049/jimmunol.1002570
发表时间：
2011
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Rahman,Saifur;Khan,ZafarK;Wigdahl,Brian;Jennings,StephenR;Tangy,Frederic;Jain,Pooja
通讯作者：
Jain,Pooja

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions.

DOI：
10.1007/s11481-015-9617-x
发表时间：
2016-03
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
0
作者：
Ginwala R;McTish E;Raman C;Singh N;Nagarkatti M;Nagarkatti P;Sagar D;Jain P;Khan ZK
通讯作者：
Khan ZK

Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation.