HIV GP120 Desensitization of T Cell Receptor Function
HIV GP120 T 细胞受体功能脱敏
基本信息
- 批准号:6496187
- 负责人:
- 金额:$ 10.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-06-01 至 2005-01-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS CD4 molecule HIV envelope protein gp120 HIV infections SCID mouse T cell receptor apoptosis biological signal transduction cellular immunity clinical research enzyme activity enzyme mechanism genetic manipulation genetically modified animals genotype helper T lymphocyte human subject hydrolysis inositol phosphates intermolecular interaction pathologic process patient oriented research phosphomonoesterases phosphorylation protein structure function protein tyrosine kinase tissue /cell culture virus cytopathogenic effect
项目摘要
DESCRIPTION: (provided by applicant) A major contributing factor in progression
of HIV disease to AIDS is the loss of functional CD4+ T cells that provide
critical helper activity for humoral and cell-mediated immune responses. It
appears that only a small, proportion of T cell loss is attributable to lytic
infection. Rather most T cells are stimulated to become antiger irresponsive
and/or to undergo apoptosis by a mechanism involving of HIV gp120-induced
CD4-mediatec transmembrane signal transduction. This response can apparently be
induced by soluble gp120, gpl2( aggregated by endogenous anti-gp 120
antibodies, HTV itself or infected cells expressing cell surface gp120. The
molecular mechanisms underlying CD4 transduction of "inhibitory" signals is
unknown. Experiments proposed in this application seek to address the molecular
basis and functional consequences of gp120 stimulated CD4 signaling.
Studies conducted during the previous period of support have led to a quantum
leap in our understanding of the inhibitory signaling circuitry activated by
gp120. They show that the SH2 domain containing jnositol 5 Phosphatase SHIP and
its effector, the adapter Downstream Qf Kiinase (Dok), which were previously
implicate in inhibitory FcyRIIB signaling, are associated with CD4fLck
complexes and are phosphorylated upon CD4 aggregation by gp 120. Further,
findings indicate that linker functions of SHIP and Dok, and enzymatic activity
of SHIP are activated by this stimulation. Finally, studies using T cells from
SHIP knockout mice demonstrate that SI-HP is required for optimal CD4-mediated
inhibition of T cell activation.
Towards elucidation of this circuitiy, we propose dissection of intermolecular
interactions among CD4/Lck, SHIP and Dok, and the regulatory function of these
interactions (aim 1). Further studies wifi define the site within TCR signaling
cascades that are the targets of SHIP and Dok (aim 2). In aim 3 we propose use
of the SCID-hu thyfliv model to directly analyze the role of SHIP and Dok in
HIV- 1 induced immunopathology ir human T cells. Finally, we will address the
role of SHIP and Dok in progression of HIV disease to AIDS (aim 4).
The studies will employ biochemical assays of signal transduction, in
conjunction with gene mutation anc deletion, and human-mouse chimera to define
structure-function relationships in the pathway. Finally, HIV infected patients
will be employed to assess the possibility that mutations/allotypic differences
which rendei this inhibitory circuit inactive may result in long term
non-progression. The studies may validate SHIP as target for discovery of
therapeutic agents for AIDS.
描述:(由申请人提供)进展的主要促成因素
艾滋病的主要原因是功能性CD 4 + T细胞的丧失,
体液和细胞介导的免疫应答的关键辅助活性。它
似乎只有一小部分T细胞损失是由于溶解性T细胞减少,
感染相反,大多数T细胞受到刺激而变得对抗原无反应
和/或通过涉及HIV gp 120诱导的机制经历细胞凋亡
CD 4介导的跨膜信号转导。这种反应显然可以
由可溶性gp 120、gp 12(由内源性抗gp 120聚集)诱导
抗体、HIV本身或表达细胞表面gp 120的感染细胞。的
CD 4转导“抑制性”信号的分子机制是
未知在本申请中提出的实验试图解决分子生物学问题。
gp 120刺激的CD 4信号传导的基础和功能后果。
在前一个支助期间进行的研究导致了一个量子
我们对抑制性信号通路的理解有了飞跃,
gp120。他们表明含有SH 2结构域的肌醇5磷酸酶SHIP和
其效应子,衔接子下游Qf Kiinase(Dok),其先前被
涉及抑制性Fc γ RIIB信号传导,与CD 4fLck相关
复合物,并在CD 4聚集时被gp 120磷酸化。此外,本发明还
研究结果表明,SHIP和Dok的连接功能,以及酶活性,
的细胞被这种刺激所激活。最后,使用T细胞的研究
SHIP基因敲除小鼠证明SI-HP是最佳的CD 4介导的
抑制T细胞活化。
为了阐明这种电路,我们提出了分子间的解剖,
CD 4/Lck,SHIP和Dok之间的相互作用,以及它们的调节功能
互动(目标1)。进一步的研究确定了TCR信号传导中的位点
作为SHIP和Dok目标的级联(目标2)。在目标3中,我们建议使用
SCID-hu thyfliv模型直接分析SHIP和Dok在
HIV- 1在人T细胞中诱导的免疫病理学。最后,我们将讨论
SHIP和Dok在HIV疾病进展为AIDS中的作用(目标4)。
这些研究将采用信号转导的生物化学测定,
结合基因突变和缺失,以及人-鼠嵌合体来定义
结构与功能的关系。最后,艾滋病病毒感染者
将用于评估突变/同种异型差异
这使这种抑制回路失活,可能导致长期的
不进步。这些研究可能会验证SHIP作为发现
用于艾滋病的治疗剂。
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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John C Cambier其他文献
Src-family kinases in B-cell development and signaling
B 细胞发育和信号转导中的 Src 家族激酶
- DOI:
10.1038/sj.onc.1208075 - 发表时间:
2004-10-18 - 期刊:
- 影响因子:7.300
- 作者:
Stephen B Gauld;John C Cambier - 通讯作者:
John C Cambier
John C Cambier的其他文献
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{{ truncateString('John C Cambier', 18)}}的其他基金
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9568080 - 财政年份:2016
- 资助金额:
$ 10.43万 - 项目类别:
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9121221 - 财政年份:2016
- 资助金额:
$ 10.43万 - 项目类别:
Insulin Specific T and B cells in Type 1 Diabetes
1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞
- 批准号:
9180031 - 财政年份:2016
- 资助金额:
$ 10.43万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
- 批准号:
8282484 - 财政年份:2012
- 资助金额:
$ 10.43万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
- 批准号:
8519291 - 财政年份:2012
- 资助金额:
$ 10.43万 - 项目类别:
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