HTLV Deregulation of CD40(L) in Cancer&Neurodegeneration

HTLV 对癌症中 CD40(L) 的失调

基本信息

项目摘要

DESCRIPTION (provided by applicant): The cellular immune response mediated by cytotoxic T lymphocytes (CTLs) plays a critical role in the identification and clearance of human T cell lymphotropic virus type I (HTLV-I)-infected cells. Functional abnormalities in CTL-based cellular immunity are thought to play a significant role in the genesis of leukemia and neuroinflammatory disease that is associated with HTLV-I infection. Whereas an inefficient CTL response likely contributes to the development of adult T cell leukemia (ATL), a hyperactive CTL compartment may mediate inflammation within the central nervous system (CNS) in individuals with HTLV-l-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The long-term goal of the proposed investigations is to define the molecular mechanisms of HTLV-I-mediated deregulation of the cellular immune response, which leads to cancer and neurologic disease. This proposal is centered on the deregulated expression of CD40 Ligand (CD40L) and its receptor CD40 in HTLV-l-infected T cells. The CD40/CD40Lsystem is critical for orchestrating both cellular and humoral immune responses. CD40L is a costimulatory molecule that is transiently expressed on activated CD4+ T cells and binds to CD40 on dendritic cells (DCs) and induces functional maturation allowing for efficient activation of antiviral CD8+ T cells. The objective of this proposal is to determine the mechanism underlying the HTLV-I-mediated deregulation of CD40 andCD40L, and the functional effects on the cellular immune response as a result of the deregulation of these immune mediators. The focus will be to determine how HTLV-I modulates cellular signaling pathways and transcriptional control mediating CD40 and CD40L gene expression. The specific aims of this proposal are to determine (1) the mechanism of CD40 transcriptional activation in HTLV-I-infected T lymphocytes; (2) the effects of CD40 on activation, proliferation and CD40L expression in HTLV-l-infected T lymphocytes; (3) the effects of HTLV-I and HTLV-I Tax on the transcriptional regulation of CD40L; and (4) the impact of deregulated expression of CD40 and CD40L on the immune response to HTLV-I. Completion of the proposed studies may lead to therapeutic strategies of immune modulation, which could prevent leukemia and/or neuroinflammatory disease.
描述(由申请方提供):细胞毒性T淋巴细胞(CTL)介导的细胞免疫应答在鉴定和清除人嗜T淋巴细胞病毒I型(HTLV-I)感染细胞中起关键作用。基于CTL的细胞免疫的功能异常被认为在与HTLV-I感染相关的白血病和神经炎性疾病的发生中起重要作用。尽管无效的CTL应答可能有助于成人T细胞白血病(ATL)的发展,但过度活跃的CTL区室可能介导患有HTLV-1相关的脊髓病/热带痉挛性下肢轻瘫(HAM/TSP)的个体中中枢神经系统(CNS)内的炎症。拟议研究的长期目标是确定HTLV-I介导的细胞免疫反应失调的分子机制,这导致癌症和神经系统疾病。该提议集中在HTLV-1感染的T细胞中CD 40配体(CD 40 L)及其受体CD 40的表达失调。CD 40/CD 40 L系统对于协调细胞和体液免疫应答至关重要。CD 40 L是一种共刺激分子,在活化的CD 4 + T细胞上瞬时表达,并与树突状细胞(DC)上的CD 40结合,诱导功能成熟,从而有效活化抗病毒CD 8 + T细胞。本研究的目的是探讨HTLV-Ⅰ介导的CD 40和CD 40 L失调的机制,以及这些免疫介质失调对细胞免疫应答的功能影响。重点将是确定HTLV-I如何调节细胞信号通路和转录调控介导的CD 40和CD 40 L基因表达。本研究的具体目的是确定(1)HTLV-1感染的T淋巴细胞中CD 40转录激活的机制;(2)CD 40对HTLV-1感染的T淋巴细胞的活化、增殖和CD 40 L表达的影响;(3)HTLV-1和HTLV-1 Tax对CD 40 L转录调节的影响;(4)CD 40和CD 40 L表达失调对HTLV-1免疫应答的影响。完成拟议的研究可能会导致免疫调节的治疗策略,这可能会预防白血病和/或神经炎性疾病。

项目成果

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EDWARD W HARHAJ其他文献

EDWARD W HARHAJ的其他文献

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{{ truncateString('EDWARD W HARHAJ', 18)}}的其他基金

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  • 批准号:
    10610829
  • 财政年份:
    2022
  • 资助金额:
    $ 2.72万
  • 项目类别:
KDR/VEGFR2 regulation of HTLV-1 oncogenesis and viral gene expression
KDR/VEGFR2 对 HTLV-1 肿瘤发生和病毒基因表达的调节
  • 批准号:
    10353507
  • 财政年份:
    2022
  • 资助金额:
    $ 2.72万
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AIP inhibition of IRF7 and innate antiviral signaling
AIP 抑制 IRF7 和先天抗病毒信号
  • 批准号:
    10217831
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
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Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1
选择性自噬受体 TAX1BP1 对先天免疫信号通路的负调节
  • 批准号:
    10276931
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
  • 项目类别:
Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1
选择性自噬受体 TAX1BP1 对先天免疫信号通路的负调节
  • 批准号:
    10797470
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
  • 项目类别:
Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1
选择性自噬受体 TAX1BP1 对先天免疫信号通路的负调节
  • 批准号:
    10622514
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
  • 项目类别:
AIP inhibition of IRF7 and innate antiviral signaling
AIP 抑制 IRF7 和先天抗病毒信号
  • 批准号:
    10393620
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
  • 项目类别:
Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1
选择性自噬受体 TAX1BP1 对先天免疫信号通路的负调节
  • 批准号:
    10414107
  • 财政年份:
    2021
  • 资助金额:
    $ 2.72万
  • 项目类别:
ZFAND6 regulation of innate antiviral immunity
ZFAND6 对先天抗病毒免疫的调节
  • 批准号:
    9979076
  • 财政年份:
    2020
  • 资助金额:
    $ 2.72万
  • 项目类别:
The role of TAX1BP1 in the innate immune response to virus infection
TAX1BP1在病毒感染先天免疫反应中的作用
  • 批准号:
    8998913
  • 财政年份:
    2015
  • 资助金额:
    $ 2.72万
  • 项目类别:
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