HUMAN DISEASE FROM FAS FAS LIGAND

FAS FAS 配体引起的人类疾病

• 批准号: 6235859
• 负责人: ALVIN E DAVIS
• 金额: $ 10.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235859
• 关键词: CD4 molecule; CD8 molecule; alleles; apoptosis; autoimmune disorder; autoimmunity; blood protein disorder; cellular pathology; child (0-11); clinical research; complementary DNA; family genetics; gene dosage; gene expression; gene mutation; human genetic material tag; human subject; messenger RNA; molecular pathology; northern blottings; nucleic acid sequence; nucleotides; polymerase chain reaction; southern blotting

This pilot project is designed to evaluate the hypothesis that certain children with generalized lymphadenopathy, hypergammaglobulinemia and preponderant CD4 CD8 T lymphocytes (double-negative T-cells, DNTs) have a genetic defect in the Fas-Fas ligand apoptosis pathway similar to that seen in the autoimmune lpr and/or gld mutant mice. Preliminary studies suggest that lymphocytes from one such child as well as his parents have abnormal mRNA expression of Fas. We propose to evaluate the expression and nucleotide sequence of the fas and fas ligand cDNAs in patients with lymphoproliferation and increased CD4 CD8 circulating cells and to determine the underlying genetic basis of the fas or fas ligand defect(s) through analysis of genomic DNA. Simultaneously, we will test functional abnormalities in peripheral lymphocyte behavior stemming from defects in the apoptotic pathway. The long term goals of these studies involving fas and fas ligand mutations include the molecular include the molecular and cellular characterization of the novel human syndrome of generalized double negative T-cell lymphoproliferation associated with autoimmunity. Accomplishment of this goal will also improve our understanding of the importance of fas gene defects in other autoimmune diseases. Human diseases caused by fas and fas ligand defects may manifest as a wide spectrum of clinical phenomena as in the mouse model. Disease expression may depend on the molecular defects i these genes, allele dosage, as well as the influence exerted by other genes involved in T cell regulation (triggering, proliferation, apoptosis, etc.). Disease in humans will also be modified by required medical interventions. Development of a screening program for patients with unexplained lymphadenopathy and/or autoimmune disease and their families would help define the prevalence and importance of fas and fas ligand gene defects in humans.

该试点项目旨在评估确定的假设 患有广义淋巴结肿大，高γ-球蛋白血症和 优势CD4 CD8 T淋巴细胞（双阴性T细胞，DNT）具有 FAS-FAS配体凋亡途径中的遗传缺陷与所见 在自身免疫性LPR和/或GLD突变小鼠中。 初步研究表明 一个这样的孩子和他的父母的淋巴细胞异常 FA的mRNA表达。 我们建议评估表达和 患有FAS和FAS配体cDNA的核苷酸序列 淋巴增生和CD4 CD8循环细胞的增加，至 确定FAS或FAS配体缺陷的基本遗传基础（S） 通过分析基因组DNA。 同时，我们将测试功能 外周淋巴细胞行为异常，源自缺陷 凋亡途径。 这些研究涉及FAS的长期目标 FAS配体突变包括分子包括分子和 新型人类综合征的细胞表征广义双重综合征 与自身免疫相关的阴性T细胞淋巴增生。 实现这一目标也将提高我们对 FAS基因缺陷在其他自身免疫性疾病中的重要性。 人类 由FA和FAS配体缺陷引起的疾病可能表现为宽 与小鼠模型一样，临床现象的光谱。 疾病表达 也可能取决于分子缺损I这些基因，等位基因剂量 由于其他涉及T细胞调节的基因所产生的影响 （触发，增殖，凋亡等）。 人类疾病也将 通过所需的医疗干预措施来修改。 筛选的发展 针对无法解释的淋巴结病和/或自身免疫的患者的计划 疾病及其家人将有助于确定患病率和重要性 人类的FA和FAS配体基因缺陷。