Regulation of Fli1 gene expression in lupus

狼疮中 Fli1 基因表达的调控

基本信息

批准号：
7279444
负责人：
TAMMY (TAMARA) NOWLING
金额：
$ 11.74万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-20 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7279444
关键词：
Address Affect Autoantibodies Autoimmune Diseases Autoimmune Process Binding Blood Disease Elements Event Gene Expression Genetic Genetic Transcription Human Inbred MRL lpr Mice Inflammatory Joints Kidney Kidney Diseases Kidney Failure Lung Lupus Lupus Erythematosus Lupus Nephritis Lymphocyte Lymphocyte Subset Molecular Morbidity - disease rate Mouse Strains Mus Myocardium Neuraxis Pathogenesis Patients Play Production Promoter Regions Rate Regulation Regulatory Element Role Skin Spleen Systemic Lupus Erythematosus T-Lymphocyte Transcription factor genes early onset improved mortality mouse model promoter transcription factor

Address Affect Autoantibodies Autoimmune Diseases Autoimmune Process Binding Blood Disease Elements Event Gene Expression Genetic Genetic Transcription Human Inbred MRL lpr Mice Inflammatory Joints Kidney Kidney Diseases Kidney Failure Lung Lupus Lupus Erythematosus Lupus Nephritis Lymphocyte Lymphocyte Subset Molecular Morbidity - disease rate Mouse Strains Mus Myocardium Neuraxis Pathogenesis Patients Play Production Promoter Regions Rate Regulation Regulatory Element Role Skin Spleen Systemic Lupus Erythematosus T-Lymphocyte Transcription factor genes early onset improved mortality mouse model promoter transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an increasingly prevalent systemic autoimmune disease affecting the joints, muscles, heart, lungs, blood, kidneys, skin and the central nervous system. Renal disease (lupus nephritis) is a common manifestation affecting up to two-thirds of lupus patients and is a major cause of morbidity and mortality. The lupus prone mouse models MRL/lpr and NZM 2410 develop an early onset autoimmune disease displaying a pathogenesis similar to that observed in human SLE with most mice dying of renal failure. Interestingly, when the transcription factor Fli1 is over-expressed in normal, healthy mice, the mice develop an autoimmune kidney disease similar to that observed in lupus prone mouse models. Subsequently, Fli1 was shown to be over-expressed in the splenic T cells of the lupus prone NZB/NZW f1 mouse strain, the spleen of lupus prone MRL/lpr mice, and lymphocytes of SLE patients. Furthermore, genetically lowering the levels of Fli1 in MRL/lpr mice by 50% significantly decreased autoantibody production, improved kidney disease and prolonged survival. Together, these studies strongly suggest that dysregulation and resulting over-expression of Fli1 plays a role in the pathogenesis of lupus. We hypothesize that the over-expression of Fli1 in lupus is a key event in the pathogenesis of lupus resulting from dysregulation of Fli1 gene transcription. To address our hypothesis we have proposed three aims. In specific aim 1 we propose to determine specifically which lymphocyte subsets in lupus prone mice over-express Fli1 compared to healthy, disease free controls. In addition we will analyze the rate of transcription and the message stability of Fli1 in lymphocyte subsets that over-express Fli1 in lupus prone mice compared to control mice. In specific aim 2 we propose to determine what cis-regulatory elements within the Fli1 promoter region are necessary for expression in control lymphocytes and what elements are involved in the over-expression in lymphocytes from lupus prone mice. For specific aim 3, we propose to identify transcription factors that bind to cis-regulatory elements in the Fli1 promoter in control lymphocytes and "disease" lymphocytes. The studies proposed in this application will further the understanding of the role of Fli1 in lupus and the molecular mechanisms involved in disease expression.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种越来越普遍的全身性自身免疫性疾病，影响关节，肌肉，心脏，肺，血液，肾脏，肾脏，皮肤和中枢神经系统。肾脏疾病（狼疮肾炎）是一种普遍的表现，影响了多达三分之二的狼疮患者，并且是发病率和死亡率的主要原因。狼疮小鼠模型MRL/LPR和NZM 2410产生了一种早期发作自身免疫性疾病，其发病机理与大多数死于肾衰竭的小鼠在人SLE中相似。有趣的是，当转录因子FLI1在正常，健康小鼠中过表达时，小鼠会形成一种自身免疫性肾脏疾病，类似于狼疮俯卧小鼠模型中的自身免疫性肾脏疾病。随后，在狼疮容易发生NZB/NZB/NZW F1小鼠菌株的脾脏T细胞中，FLI1被表达过表达，狼疮pro鼠MRL/LPR小鼠的脾脏和SLE患者的淋巴细胞。此外，从遗传上将MRL/LPR小鼠的FLI1水平降低了50％，可显着降低自身抗体的产生，改善肾脏疾病和长期生存率。总之，这些研究强烈表明，FLI1的失调和导致的过表达在狼疮的发病机理中起作用。我们假设狼疮中Fli1的过表达是狼疮发病机理的关键事件，这是由于FLI1基因转录失调引起的。为了解决我们的假设，我们提出了三个目标。在特定的目标1中，我们建议特定确定狼疮小鼠中哪些淋巴细胞亚群过表达FLI1与健康的无疾病对照相比。此外，我们将分析与对照小鼠相比，在狼疮小鼠中过表达FLI1的淋巴细胞子集中FLI1的转录速率和消息稳定性。在特定的目标2中，我们建议确定FLI1启动子区域内哪些顺式调节元件对于对照淋巴细胞的表达以及来自狼疮小鼠的淋巴细胞过表达涉及哪些元素。对于特定目标3，我们建议鉴定对照淋巴细胞和“疾病”淋巴细胞中FLI1启动子中与顺式调节元件结合的转录因子。本应用中提出的研究将进一步了解FLI1在狼疮中的作用以及涉及疾病表达的分子机制。