Exploring How HTLV-1 Tax Induces T Cell Leukemia
探索 HTLV-1 税如何诱导 T 细胞白血病
基本信息
- 批准号:6917935
- 负责人:
- 金额:$ 44.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-07-01 至 2007-06-30
- 项目状态:已结题
- 来源:
- 关键词:I kappa B betaamidohydrolasesbiological signal transductioncAMP response element binding proteingenetically modified animalshuman T cell leukemiahuman T cell lymphotropic virus type 1laboratory mousenuclear factor kappa betap53 gene /proteinphosphorylationtranscription factorviral carcinogenesisvirus related neoplasm /cancer
项目摘要
DESCRIPTION (provided by applicant): The type I human T cell leukemia virus (HTLV-I) is a complex type C retrovirus etiologically linked with several diverse human diseases including: (1) the Adult T Cell Leukemia (ATL), an aggressive and usually fatal neoplastic expansion of activated CD4+ T lymphocytes; (2) Tropical Spastic Paraparesis/HTLV-I associated myelopathy (TSP/HAM), a progressive neurodegenerative process involving the spinal cord; and (3) a variety of poorly understood autoimmune or inflammatory diseases that affect different end organs including the eye, salivary glands, joints, and muscle. The molecular basis for HTLV-I transformation of human CD4+ T lymphocytes remains unclear, however, the pX-encoded Tax gene product appears to play a central role. Tax both enhances viral replication and deregulates the expression of various host cell genes by altering the activity of select host transcription factors including NF-kappaB/Rel and CREB/ATF. To define the molecular events associated with full T cell transformation, we will utilize Tax expressing transgenic mice that develop T-cell lymphomas closely resembling ATL. Transgenic animals expressing mutants of Tax that are selectively impaired for NF-kappaB/Rel or CREB/ATF dependent gene expression will be evaluated to define the role played by each of these individual transcription factor pathways in T cell transformation. We will further assess the requirement for continuous Tax or NF-kappaB/Rel expression for maintenance of Tax induced tumors by preparing and studying transgenic animals conditionally expressing Tax or a nondegradable mutant of IkappaBalpha that potently inhibits NF-kappaB/Rel activation by Tax (Specific Aim 1). In a second line of study, we will explore how Tax activates the NF-kappaB/Rel family of transcription factors, following its physical assembly with the IKKgamma subunit of the signalsome complex. The potential recruitment of upstream kinases to the signalsome by Tax and the potential role of Tax oligomerization will be assessed. In related studies, we will test whether the inactivation of the p53 tumor suppressor by Tax involves phosphorylation by the IKK complex. (Specific Aim 2). In a third line of experimentation, we will investigate how Tax induces the sustained, long-term nuclear expression of NF-kappaB, which differs sharply from transient response elicited by physiological stimuli. We will specifically examine whether Tax subverts the generation of negative signals within the IKK complex that normally terminates signalsome action. Additionally, we will explore the potential interplay of Tax with a newly recognized negative pathway of nuclear NF-kappaB regulation involving deacetylation of RelA by histone deacetylase 3. Such deacetylation promotes the rapid nuclear export of RelA and contributes to termination of the NF-kappaB response (Specific Aim 3). Through these combined in vivo and in vitro experiments, we hope to gain key insights into the molecular events underlying HTLV-I Tax mediated leukemogenesis.
描述(由申请人提供):I型人T细胞白血病病毒(HTLV-I)是一种复杂的C型逆转录病毒,与几种不同的人类疾病有病因学联系,包括:(1)成人T细胞白血病(ATL),激活CD4+ T淋巴细胞的侵袭性和通常致命的肿瘤扩张;(2)热带痉挛性麻痹/HTLV-I相关脊髓病(TSP/HAM),一种累及脊髓的进行性神经退行性过程;(3)影响不同终末器官(包括眼睛、唾液腺、关节和肌肉)的各种尚不清楚的自身免疫或炎症性疾病。HTLV-I转化人类CD4+ T淋巴细胞的分子基础尚不清楚,然而,px编码的Tax基因产物似乎起着核心作用。通过改变宿主转录因子(包括NF-kappaB/Rel和CREB/ATF)的活性,Tax既可以增强病毒复制,又可以调节多种宿主细胞基因的表达。为了确定与完全T细胞转化相关的分子事件,我们将利用表达Tax的转基因小鼠发展成与ATL非常相似的T细胞淋巴瘤。将对表达Tax突变体的转基因动物进行评估,这些突变体选择性地损害NF-kappaB/Rel或CREB/ATF依赖基因的表达,以确定这些单独的转录因子通路在T细胞转化中所起的作用。我们将通过制备和研究有条件表达Tax或IkappaBalpha不可降解突变体的转基因动物来进一步评估维持Tax诱导肿瘤对持续表达Tax或NF-kappaB/Rel的需求(Specific Aim 1)。该突变体可有效抑制Tax对NF-kappaB/Rel的激活。在第二项研究中,我们将探索Tax如何激活NF-kappaB/Rel转录因子家族,在其与信号体复合体的IKKgamma亚基的物理组装之后。我们将对上游激酶被Tax募集到信号体的可能性以及Tax寡聚化的潜在作用进行评估。在相关研究中,我们将测试Tax对p53肿瘤抑制因子的失活是否涉及IKK复合物的磷酸化。(具体目标2)。在第三条实验线中,我们将研究Tax如何诱导NF-kappaB的持续、长期核表达,这与生理刺激引起的短暂反应有很大不同。我们将特别研究Tax是否会破坏IKK复合体中通常终止信号体作用的负面信号的产生。此外,我们将探索Tax与新发现的核NF-kappaB调控的负通路的潜在相互作用,该通路涉及组蛋白去乙酰化酶3对RelA的去乙酰化。这种去乙酰化促进RelA的快速核输出,并有助于NF-kappaB反应的终止(Specific Aim 3)。通过这些结合体内和体外实验,我们希望获得HTLV-I Tax介导的白血病发生的分子事件的关键见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Warner C. Greene其他文献
Cytochalasin binding in lymphocytes and polymorphonuclear leukocytes.
淋巴细胞和多形核白细胞中的细胞松弛素结合。
- DOI:
- 发表时间:
1976 - 期刊:
- 影响因子:3.7
- 作者:
C. Parker;Warner C. Greene;Hanna H. MacDonald - 通讯作者:
Hanna H. MacDonald
Interleukin 2-induced tyrosine phosphorylation. Interleukin 2 receptor beta is tyrosine phosphorylated.
白细胞介素2诱导的酪氨酸磷酸化。
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:4.8
- 作者:
Gordon B. Mills;Christopher May;Martha McGill;Marion Fung;Michael Baker;Robert Sutherland;Warner C. Greene - 通讯作者:
Warner C. Greene
A role for cytochalasin-sensitive proteins in the regulation of calcium transport in activated human lymphocytes
- DOI:
10.1016/s0006-291x(75)80169-0 - 发表时间:
1975-07-22 - 期刊:
- 影响因子:
- 作者:
Warner C. Greene;Charles W. Parker - 通讯作者:
Charles W. Parker
Analysis of Interleukin-2-dependent Signal Transduction through the Shc/Grb2 Adapter Pathway: INTERLEUKIN-2-DEPENDENT MITOGENESIS DOES NOT REQUIRE Shc PHOSPHORYLATION OR RECEPTOR ASSOCIATION
- DOI:
10.1074/jbc.270.48.28858 - 发表时间:
1995-12-01 - 期刊:
- 影响因子:
- 作者:
Gerald A. Evans;Mark A. Goldsmith;James A. Johnston;Weiduan Xu;Sarah R. Weiler;Rebecca Erwin;O. M. Zack Howard;Robert T. Abraham;J. O'Shea John;Warner C. Greene;William L. Farrar - 通讯作者:
William L. Farrar
A second human interleukin-2 binding protein that may be a component of high-affinity interleukin-2 receptors
一种可能是高亲和力白介素-2 受体成分的第二种人类白介素-2 结合蛋白
- DOI:
10.1038/327518a0 - 发表时间:
1987-06-11 - 期刊:
- 影响因子:48.500
- 作者:
Mitchell Dukovich;Yuji Wano;Le thi Rich Thuy;Paul Katz;Bryan R. Cullen;John H. Kehrl;Warner C. Greene - 通讯作者:
Warner C. Greene
Warner C. Greene的其他文献
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{{ truncateString('Warner C. Greene', 18)}}的其他基金
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期
- 批准号:
10237149 - 财政年份:2019
- 资助金额:
$ 44.7万 - 项目类别:
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期
- 批准号:
10006808 - 财政年份:2019
- 资助金额:
$ 44.7万 - 项目类别:
Assessing the root causes of chronic inflammation in HIV-infected individuals using drugs of abuse
评估使用滥用药物的艾滋病毒感染者慢性炎症的根本原因
- 批准号:
9761514 - 财政年份:2017
- 资助金额:
$ 44.7万 - 项目类别:
Project 2: Delineating virus and host cell-derived biomarkers predicting time to HIV rebound after treatment interruption
项目 2:描绘病毒和宿主细胞衍生的生物标志物,预测治疗中断后 HIV 反弹的时间
- 批准号:
10223996 - 财政年份:2017
- 资助金额:
$ 44.7万 - 项目类别:
Exploiting the Host-HIV Interface To Identify Biomarkers Predicting Time to Viral Rebound after Treatment Interruption
利用宿主-HIV 界面识别生物标志物,预测治疗中断后病毒反弹的时间
- 批准号:
9754763 - 财政年份:2017
- 资助金额:
$ 44.7万 - 项目类别:
HIV without AIDS: A Radically Different Approach to Help the Developing World
没有艾滋病的艾滋病毒:帮助发展中国家的完全不同的方法
- 批准号:
9503875 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
HIV without AIDS: A Radically Different Approach to Help the Developing World
没有艾滋病的艾滋病毒:帮助发展中国家的完全不同的方法
- 批准号:
8606334 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
HIV without AIDS: A Radically Different Approach to Help the Developing World
没有艾滋病的艾滋病毒:帮助发展中国家的完全不同的方法
- 批准号:
8856536 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
HIV-Induced CD4 T-Cell Depletion: An Innate Host Defense Gone Awry?
HIV 诱导的 CD4 T 细胞耗竭:先天宿主防御出了问题?
- 批准号:
8411054 - 财政年份:2012
- 资助金额:
$ 44.7万 - 项目类别:
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