CONTROL OF INTERLEUKIN-2 IN SJOGREN'S SYNDROME

干燥综合征中白细胞介素 2 的控制

• 批准号: 3223102
• 负责人: NORMAN TALAL
• 金额: $ 12.64万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3223102
• 关键词: DNA binding protein; Sjogren's syndrome; T lymphocyte; antiinflammatory agents; biological signal transduction; calcium flux; gel mobility shift assay; gene expression; genetic regulation; human subject; interleukin 2; leukocyte activation /transformation; medical complication; messenger RNA; molecular pathology; polymerase chain reaction; salivary glands; transcription factor

Sjogren's syndrome (SS) is characterized by lymphocytic infiltration of the salivary glands leading to a variety of dental complications. This project focuses on molecular abnormalities in IL-2 biology involving SS T cells. T lymphocytes from SS peripheral blood are hyporesponsive to mitogenic and antigenic stimuli, whereas T lymphocytes infiltrating the SS salivary glands actively produce IL-2. Some of these are older observations based on cell activation markers; others are recent findings from our own laboratory measuring transcription factors or using PCR amplification in SS salivary gland tissue. The current specific aims which follow are designed to further analyze abnormalities of signal transduction in relation to a defect in the Oct. 1 transcription factor necessary for IL-2 gene activation, to continue our analysis of cytokine profiles using PCR, and to develop new therapeutic modalities for SS. Specific aims: 1. The expression of nuclear proteins binding to cognate DNA sequences in the IL-2 gene promoter region (transcription factors) will be assessed by electrophoretic mobility shift assay. This signaling event is putatively the most distal in the pathway. Therefore, abnormalities detected would support our hypothesis that an early signaling defect in calcium contributes to the reduced biosynthesis of IL-2. 2. Specific mRNAs for the gene encoding IL-2 will be studied in SS salivary glands using the PCR. Demonstration of inflammatory cytokines such as IL-2 in SS tissues could provide an explanation for the intense lymphocytic infiltration and tissue destruction. 3. Normalization of IL-2 biosynthesis, as well as the expression of proteins involved in the regulation of the IL-2 gene, will be attempted using drugs known to enhance T cell activation. Aspirin-like drugs that enhance L-2 production and both early and late signaling events will be studied.

干燥综合征（SS）的特征是淋巴细胞浸润， 唾液腺导致各种牙科并发症。 这 该项目的重点是涉及SS的IL-2生物学分子异常 T细胞。 SS外周血T淋巴细胞对 促有丝分裂和抗原刺激，而T淋巴细胞浸润 SS唾液腺主动产生IL-2。 其中一些更古老 基于细胞活化标记的观察;其他是最近的发现 从我们自己的实验室测量转录因子或使用PCR SS唾液腺组织扩增。 目前的具体目标 其被设计为进一步分析信号的异常 与Oct.1转录因子缺陷相关的转导 IL-2基因激活所必需的，继续我们的细胞因子分析， 使用PCR的轮廓，并开发新的治疗方式的SS。 具体目标： 1. 与同源DNA序列结合的核蛋白的表达 将评估IL-2基因启动子区（转录因子）中的 通过电泳迁移率变动分析。 这个信号事件是 推定为路径的最远端。 因此， 这一发现将支持我们的假设，即早期信号缺陷， 钙有助于降低IL-2的生物合成。 2. 将在SS中研究编码IL-2的基因的特异性mRNA。 唾液腺的PCR检测。 炎性细胞因子的证明 如SS组织中的IL-2可以解释这种强烈的 淋巴细胞浸润和组织破坏。 3. IL-2生物合成的正常化，以及 参与IL-2基因调控的蛋白质，将尝试 用的是能增强T细胞活化的药物 阿司匹林样药物， 增强L-2的产生，并且早期和晚期信号事件都将被 研究了