FAS MRNA EDITING AND POLYMORPHISMS IN SLE PATIENTS

SLE 患者中的 FAS mRNA 编辑和多态性

• 批准号: 6413209
• 负责人: JIANMING WU
• 金额: $ 11.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413209
• 关键词: CD95 molecule; clinical research; frameshift mutation; genetic polymorphism; human subject; messenger RNA; polymerase chain reaction; rheumatoid arthritis; systemic lupus erythematosus

Human systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with involvement of multiple organ systems and extremely diverse clinical manifestation. SLE appears to involve the emergence and activation of both autoreactive T cells and B cells. Our preliminary data suggest that Fas (CD95) mRNA has been modified in SLE patients. The first Fas mRNA modification (or editing) resulted in an insertion of A after nucleotide 1114 (Genbank accession number X63717) that leads to a frameshift mutation in the Fas coding region and disruption of the death domain in Fas protein. Up to 26% of edited Fas mRNA has been found in SLE patients. The second Fas mRNA editing event resulted in a T to C substitution at nucleotide position 1173 that leads to an amino acid change from isoleucine to threonine mutation within the death domain of Fas protein. The latter editing event has been detected both in SLE patients and non-SLE controls. Furthermore, we have also detected two non-synonymous polymorphisms in a group of SLE patients. The first non-synonymous polymorphism occurs at the Fas signal sequence cleavage site and the second non-synonymous polymorphism is within the Fas transmembrane domain. These Fas polymorphisms potentially will alter Fas biological functions. Accordingly, the overall goals of this project are to identify and characterize mutations resulting from Fas mRNA editing in SLE patients and from novel Fas gene polymorphisms and to determine whether these mutations and polymorphisms in Fas have an impact on the pathogenesis of SLE. These goals will be achieved through the following specific aim: 1) to confirm the existence of altered Fas mRNA editing products and their impact on Fas protein expression and on Fas functions; 2) to investigate whether the editing of Fas mRNA occurs uniquely in SLE or occurs also in other inflammatory diseases; 3) to detect and characterize Fas coding region non-synonymous polymorphisms and/or mutations in SLE population; 4) to establish the potential role of Fas mRNA editing and polymorphisms or mutations in human SLE pathogenesis. Elucidation of the biological roles of Fas editing and polymorphisms in the pathogenesis of SLE will aid the development of new therapeutic a roaches for SLE.

人类系统性红斑狼疮（SLE）是一种典型的系统性红斑狼疮， 自身免疫性疾病，累及多个器官系统， 临床表现极为多样。SLE似乎涉及 自身反应性T细胞和B细胞的出现和激活。我们 初步数据表明Fas（CD 95）mRNA在SLE中被修饰， 患者第一个Fas mRNA修饰（或编辑）导致插入 核苷酸1114后的A（Genbank登录号X63717），导致 Fas编码区发生移码突变， 结构域。在SLE中发现高达26%的编辑的Fas mRNA 患者第二次Fas mRNA编辑事件导致T到C的替换 在核苷酸位置1173处，其导致从异亮氨酸 Fas蛋白死亡结构域内的苏氨酸突变。后者 在SLE患者和非SLE对照中均检测到编辑事件。 此外，我们还检测到两个非同义的多态性， SLE患者组。第一个非同义多态性发生在 Fas信号序列切割位点和第二个非同义 多态性在Fas跨膜结构域内。这些Fas 多态性可能改变Fas的生物学功能。因此，委员会认为， 该项目的总体目标是识别和表征突变 SLE患者Fas mRNA编辑和新Fas基因 多态性，并确定这些突变和多态性是否 Fas在SLE发病中的作用。这些目标将是 通过以下具体目标实现：1）确认存在 Fas mRNA编辑产物的改变及其对Fas蛋白表达的影响 2）探讨Fas mRNA的编辑是否与Fas基因的功能有关， 仅发生在SLE中或也发生在其他炎性疾病中; 3） 检测和表征Fas编码区非同义多态性 和/或SLE人群中的突变; 4）确定Fas的潜在作用 人类SLE发病机制中的mRNA编辑和多态性或突变。 阐明Fas编辑和多态性在肿瘤细胞中的生物学作用。 SLE的发病机制将有助于开发新的治疗方法， SLE。