Genetic Dissection of the defect in the SLAM-receptor.........

SLAM 受体缺陷的基因剖析.........

• 批准号: 7135752
• 负责人: CORNELIS P TERHORST
• 金额: $ 26.35万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135752
• 关键词: antigen presentation; bioengineering /biomedical engineering; biological signal transduction; cell surface receptors; chromatin; gene deletion mutation; genetic recombination; genetic screening; genetic susceptibility; genetic transcription; genetically modified animals; genotype; helper T lymphocyte; immune tolerance /unresponsiveness; immunophenotype; laboratory mouse; leukocyte activation /transformation; method development; single nucleotide polymorphism; systemic lupus erythematosus; transfection

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against a wide spectrum of self-antigens, especially from the cell nucleus. Genetic predisposition is an important contributor to susceptibility to SLE in both humans and animals. Genes in multiple pathways participate in mediating disease pathogenesis, and epistatic interactions amongst these genes influence the severity of disease. One group includes genes whose products are active in physiologic pathways of waste disposal mechanisms in the body, and includes genes involved in removal of circulating immune complexes and apoptotic cells by the mononuclear phagocyte system. The second group encodes genes that regulate thresholds for tolerance and activation of T and B lymphocytes. This project is part of an interactive PPG, which seeks to address the overall hypothesis that mutations in one or more of the seven SLAM-family genes affect pathways that contribute to tolerance to selfantigens in humans and mice. Collectively, our observations made in humans and mice strongly support this Specifically we will: Aim 1. test the hypothesis that the SLAM-Family-locus {CD244<->Ly108} governs CD4 T cell and antigen presenting cell functions in the C57BL/6 mouse. Aim 2.test the hypothesis that deletion of the {CD244<->Ly108} genomic interval causes loss of tolerance toward chromatin in C57BL/6 mice. Aim 3.test the hypothesis that SLAM-family genes derived from 129Sv mice contribute to the development of lupus upon introduction into the {CD244<->Ly108}-/- C57BL/6 mouse. Together these experiments should clarify the interplay between APC, T and B cells governed by the SLAM-Family genes and their control of susceptibility to murine lupus. The results of these studies should suggest therapeutic strategies that can be applied to SLE patients.

系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是产生 针对多种自身抗原（尤其是来自细胞核的自身抗原）的自身抗体。遗传 易感性是人类和动物患系统性红斑狼疮的重要因素。基因在 多种途径参与介导疾病发病机制，以及这些途径之间的上位相互作用 基因影响疾病的严重程度。一组包括其产物活跃的基因 体内废物处理机制的生理途径，包括参与清除的基因 单核吞噬细胞系统循环免疫复合物和凋亡细胞。第二个 组编码调节 T 和 B 淋巴细胞耐受和激活阈值的基因。 该项目是交互式 PPG 的一部分，旨在解决突变的总体假设 七个 SLAM 家族基因中的一个或多个影响有助于自身抗原耐受的途径 在人类和小鼠中。总的来说，我们对人类和小鼠的观察结果强烈支持 这 具体来说，我们将： 目标 1. 检验 SLAM-Family-locus {CD244<->Ly108} 控制 CD4 T 细胞和抗原的假设 展示 C57BL/6 小鼠的细胞功能。 目标 2.检验删除 {CD244<->Ly108} 基因组区间导致耐受性丧失的假设 C57BL/6 小鼠中的染色质。 目标 3.检验来自 129Sv 小鼠的 SLAM 家族基因有助于发育的假设 引入{CD244<->Ly108}-/-C57BL/6小鼠后狼疮的发生。 这些实验共同阐明了 APC、T 细胞和 B 细胞之间的相互作用，这些细胞受 SLAM-家族基因及其对小鼠狼疮易感性的控制。这些研究的结果应该 提出可应用于 SLE 患者的治疗策略。