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假设， 全身性淋巴结病、高丙种球蛋白血症和 占优势的CD 4 CD 8 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相似 在自身免疫性LPR和/或GLD突变小鼠中。 初步研究表明 来自这样一个孩子的淋巴细胞以及他的父母有异常的 Fas mRNA表达。 我们建议对表达式求值， 胃癌患者Fas和Fas配体cDNA的核苷酸序列 淋巴细胞增殖和CD 4 CD 8循环细胞增加， 确定Fas或Fas配体缺陷的潜在遗传基础 通过基因组DNA的分析。 同时，我们将测试功能 外周淋巴细胞行为异常， 凋亡途径。 这些涉及fas的研究的长期目标 和Fas配体突变包括分子， 新的人类泛发性双重综合征的细胞特征 与自身免疫相关的阴性T淋巴细胞增生。 实现这一目标还将增进我们对 Fas基因缺陷在其他自身免疫性疾病中的重要性。 人类 由Fas和Fas配体缺陷引起的疾病可以表现为广泛的 如小鼠模型中的临床现象谱。 疾病表达 可能取决于这些基因中的分子缺陷，等位基因剂量，以及 与其他参与T细胞调节的基因一样， （触发、增殖、凋亡等）。 人类的疾病也会 通过所需的医疗干预进行修改。 筛选的发展 不明原因淋巴结病和/或自身免疫性疾病患者计划 疾病及其家庭将有助于确定患病率和重要性， fas和fas配体基因缺陷。