Regulation of CD154 Expression

CD154 表达的调节

• 批准号: 7653268
• 负责人: WILLIAM FREDERICK CARSON RIGBY
• 金额: $ 39.14万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653268
• 关键词: 3' Untranslated Regions; Alleles; Anabolism; Autoimmunity; Basic Science; Binding; Development; Dinucleotide Repeats; Elements; Etiology; Gene Expression; Genetic; Heterodimerization; Heterogeneous-Nuclear Ribonucleoprotein L; Immune; Immune response; Mediating; Messenger RNA; Modeling; Pathway interactions; Play; Polyadenylation Pathway; Polypyrimidine Tract-Binding Protein; Process; Proteins; Regulation; Rheumatoid Arthritis; Role; Systemic Lupus Erythematosus; TNFSF5 gene; Toxic effect; Translational Regulation; Untranslated Regions; neutrophil; novel; overexpression; therapeutic target

CD154 overexpression is a hallmark of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The etiology of the overexpression of this critical immune molecule is not understood. Second, the targeting of CD154 by antibody·based approaches is limited by toxicity. These two issues underscore the need for better understanding of the regulation of CD154 biosynthesis. We have established the role of polypyrimidine tract binding (PTS) proteins in mediating CD154 mRNA turnover through binding to a 3'UTR CU·rich element (CURE). These studies uncovered a novel pathway of translational regulation through a polymorphic CA repeat found in the CD154 3'UTR which regulates CD154 mRNA polyadenylation. We refer to this novel cis·acting element, consisting of CA dinucleotide repeats, as the CA·rich element (CARE). Importantly, the CD153'UTR CA repeats are polymorphic with certain alleles associated with CD154 overexpression and the development of RA and SLE.

CD154过表达是类风湿关节炎（RA）和全身性红斑狼疮（SLE）的标志。该关键免疫分子的过表达的病因尚不清楚。其次，基于抗体的方法将CD154的靶向受到毒性的限制。这两个问题强调了需要更好地理解CD154生物合成调节的必要性。我们已经确定了通过与3'Utr Cu·富元素（治愈）结合的结合，息肉酰胺氨基氨基氨结合（PTS）蛋白在介导CD154 mRNA转换中的作用。这些研究发现了通过在CD154 3'UTR中发现的多态性CA重复进行转化调节的新途径，该重复调节CD154 mRNA聚腺苷酸化。我们将这种新颖的顺式作用元素（由CA二核苷酸重复序列组成），为CA·丰富元素（CARE）。重要的是，CD153'UTR CA重复序列是多态性的，与CD154过表达相关的某些等位基因以及RA和SLE的发展。