T CELLS AND AGING

T 细胞与衰老

• 批准号: 2704312
• 负责人: JORG J GORONZY
• 金额: $ 19.65万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2704312
• 关键词: B lymphocyte; CD28 molecule; CD4 molecule; CD40 molecule; DNA binding protein; DNA footprinting; T cell receptor; aging; cell senescence; clinical research; gene expression; genetic regulatory element; genetic susceptibility; genetic transcription; helper T lymphocyte; human subject; immunologic memory; immunosenescence; molecular cloning; southern blotting; transfection

DESCRIPTION (Adapted from the Applicant's Abstract): Aging is associated with important clinical problems such as increased susceptibility to infections and certain malignancies. Mechanisms underlying immunosenescence are not completely understood but evidence has been collected that T cell function declines in the elderly. The investigators have made the observation that, in a subset of aged individuals, CD4+ T cells have lost the expression of the important co-stimulatory molecule, CD28. Susceptibility to losing CD28 expression appears to be genetically determined and occurs in about 30% of the Caucasian population. The investigators have also shown that CD4+ CD28 null T cells are deficient in the expression of CD40 ligand (CD40L) and therefore lack a second critical molecule that is important in facilitating T-B cell interactions and the development of humoral immune responses. Preliminary data indicate that the downregulation of CD28 on CD4+ T cells is caused by a transcriptional block. The investigators have evidence that two possibly novel nuclear DNA binding activities correlate with CD28 expression and that the presence of these binding activities is age dependent. The investigators propose that the loss of CD28 is a critical event in immunosenescence and that understanding mechanisms of CD28 gene expression will provide novel agents for interventions intended to correct immune hyporesponsiveness in the elderly. The investigators are planning to examine the basal transcriptional machinery regulating CD28 gene expression and to identify the cis-acting elements required for CD28 expression. The investigators will continue their studies aimed at defining the binding motifs within a 67 bp segment and to molecularly characterize the corresponding DNA binding proteins that have been shown to correlate with CD28 expression. The investigators propose to clone and sequence the corresponding genes and to confirm differential expression in CD28+ and CD28null T cells. The influence of senescence on the expression of these proteins will be analyzed in vitro after replicative senescence as well as in vivo by comparing young and old individuals. Finally, the investigators will pursue the question whether CD40L expression can be restored by reconstituting CD28 expression in deficient T cells. This question will be examined by comparing helper cell functions of CD4+ CD28null and CD4+ CD28null T cell clones derived from the same progenitor cell and by transfecting CD28-deficient CD4+ T cell clones with the CD28 gene. Studying molecular and functional aspects of CD4+ CD28null T cells provides a unique opportunity to address age- related dysfunction in T cells. Preventing the accumulation of CD4+ CD28null T cells might be a primary target for immune therapy in aging individuals.

描述（根据申请人的摘要改编）：老化是相关的 存在重要的临床问题，例如增加对 感染和某些恶性肿瘤。 免疫衰老的基础机制 尚未完全理解，但已经收集了T细胞的证据 职能在老年人中下降。 调查人员使 观察到，在老年人的子集中，CD4+ T细胞丢失了 重要的共刺激分子CD28的表达。 失去CD28表达的敏感性似乎是遗传的 确定并发生在大约30％的高加索人群中。 这 研究人员还表明，CD4+ CD28无效T细胞缺乏 CD40配体（CD40L）的表达，因此缺乏第二个临界 对于促进T-B细胞相互作用和 体液免疫反应的发展。 初步数据表明 CD4+ T细胞上CD28的下调是由转录块引起的。 研究人员有证据表明两个可能是新颖的核DNA结合 活动与CD28的表达相关，并且存在这些活动 约束活动取决于年龄。 调查人员建议 CD28的损失是免疫衰变和理解的关键事件 CD28基因表达的机制将为 旨在纠正老年人免疫反应性的干预措施。 调查人员计划检查基础转录 调节CD28基因表达并识别顺式作用的机械 CD28表达所需的元素。 调查人员将继续 他们的研究旨在定义67 bp段内的结合基序 并以分子表征相应的DNA结合蛋白 已显示与CD28表达相关。 调查人员 提议克隆并测序相应的基因并确认 CD28+和CD28NULL T细胞中的差异表达。 影响 这些蛋白质表达的衰老将在体外分析 在复制衰老和体内进行比较之后 个人。 最后，调查人员将提出一个问题 CD40L表达可以通过重建CD28表达来恢复 缺乏T细胞。 该问题将通过比较助手单元进行检查 CD4+ CD28NULL和CD4+ CD28NULL T细胞克隆的功能 相同的祖细胞和通过转染CD28缺陷CD4+ T细胞克隆 与CD28基因。 研究CD4+的分子和功能方面 CD28NULL T细胞提供了解决与年龄相关的独特机会 T细胞功能障碍。 防止CD4+ CD28NULL T的积累 细胞可能是衰老个体免疫治疗的主要靶标。