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SIGNAL TRANSDUCTION VIA THE CD4 MOLECULE

通过 CD4 分子进行信号转导

基本信息

批准号：
2064344
负责人：
STEVEN M NEUDORF
金额：
$ 10.64万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 1995-03-31
项目状态：
已结题

项目摘要

This proposal describes the characteristics of a monoclonal antibody, termed 6B10, that binds to a portion of the CD4 molecule involved in the binding of the HIV/AIDS virus. The binding of 6B10 to CD4+ T cells also results in the generation of biochemical signals important in lymphocyte activation, namely the mobilization of intracellular calcium (CA++). This occurs in the absence of the CD3/TCR complex suggesting that the CD4 molecule is directly involved in the transduction of these biochemical signals. 6B10 also inhibited OKT3/CD3-induced T cell proliferation and OKT3/CD3- induced Ca++ mobilization. This suggests that signal transduction by CD4 may be important in the regulation of T cell proliferation. Since 6B10 binds to a region of CD4 involved in HIV binding, it is therefore hypothesized that HIV may initiate Ca++ mobilization. If HIV affects T cell function in a manner similar to that seen by 6B10, this would suggest involvement of HIV in T cell activation and may help explain the pathogenesis of some of the qualitative abnormalities of CD4+ T cells seen in patients with AIDS. This hypothesis will be investigated by comparing the effects of HIV to 6B10 in terms of their ability to induce changes in Ca as well as affect T cell proliferation, IL-2 production and IL-2 receptor expression. The region of the CD4 molecule important in the generation of these biochemical signals will also be determined. This will be done using site-directed mutagenesis to alter portions of the cDNA coding for the intracytoplasmic tail of the CD4 molecule. Mutant cDNA's will be inserted in the CD4- T cell line, Jurkat, and studied in terms of Ca++ mobilization as well as in IL-2 production and IL-2 receptor expression. The understanding of how the CD4 molecule affects the biochemical events of lymphocyte activation may lead to an improved understanding of the interactions between HIV and CD4 involved in the pathogenesis of the immunodeficiency seen in patients with AIDS.

该建议描述了单克隆抗体的特征，一种称为6 B10的抗体，与CD 4分子的一部分结合参与了艾滋病毒的结合。 6 B10的结合与CD 4 + T细胞接触也会导致产生生化反应，淋巴细胞活化中的重要信号，即动员细胞内钙（CA++）。这是在没有 CD 3/TCR复合物，表明CD 4分子直接参与这些生化信号的传导。 6B10 还抑制OKT 3/CD 3诱导的T细胞增殖和OKT 3/CD 3- 诱导Ca++动员。这表明信号传导在调节T细胞增殖中可能是重要的。由于6 B10与参与HIV结合的CD 4区域结合，因此假设艾滋病毒可能启动Ca++动员。如果艾滋病毒以类似于免疫缺陷病毒的方式影响T细胞功能， 6 B10，这表明HIV参与T细胞活化并可能有助于解释一些定性的在艾滋病患者中观察到的CD 4 + T细胞异常。这将通过比较艾滋病毒的影响， 6 B10诱导Ca变化的能力以及影响T细胞增殖、IL-2产生和IL-2受体表情 CD 4分子的区域在免疫系统中起重要作用。还将测定这些生化信号的产生。这将使用定点诱变来改变部分编码CD 4胞质内尾区的cDNA 分子。将突变cDNA插入CD 4- T细胞系中， Jurkat，并在Ca++动员以及 IL-2产生和IL-2受体表达。的理解关于CD 4分子如何影响淋巴细胞活化可能会导致更好的理解 HIV和CD 4之间的相互作用参与了艾滋病患者的免疫缺陷。