The role of Fli1 in the pathogenesis of lupus

Fli1在狼疮发病机制中的作用

• 批准号: 7194443
• 负责人: TAMMY (TAMARA) NOWLING
• 金额: $ 7.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194443
• 关键词: Acute Erythroblastic Leukemia; Adult; Affect; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Binding Sites; Blood Vessels; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cell Lineage; DNA Binding Domain; Data; Development; Disease; Disease Outcome; Disease Progression; Embryo; Embryonic Development; Essential Genes; Event; Family; Fibronectins; Foundations; Friend Murine Leukemia Virus; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Heart; Hematopoietic; Hemorrhage; Human; Immune system; Inbred MRL lpr Mice; Inflammatory; Kidney Diseases; Kidney Failure; Knowledge; Lung; Lupus; Lupus Nephritis; Lymphocyte; Lymphocyte Function; Lymphoid; Mature B-Lymphocyte; Mature T-Lymphocyte; Mediating; Megakaryocytes; Messenger RNA; Methods; Molecular; Mouse Strains; Mus; Neural tube; Ovary; Pathogenesis; Patients; Play; Production; Promoter Regions; Proteins; Proto-Oncogenes; Regulation; Regulatory Pathway; Research; Rest; Role; Site; Spleen; Suppressor-Effector T-Lymphocytes; Systemic Lupus Erythematosus; Systems Analysis; T-Lymphocyte; Testing; Tissues; Trans-Activators; Transcription factor genes; Transcriptional Regulation; Transgenic Mice; design; early onset; granulocyte; hematopoietic tissue; immune function; improved; in utero; member; monocyte; mouse model; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Lupus prone mouse model MRL/lpr develop an early onset autoimmune disease displaying a pathogenesis similar to that observed in human SLE with most mice dying of renal failure. Normal mice develop an autoimmune kidney disease similar to that observed in lupus prone mouse models in which the Ets transcription factor Fli1 has been over-expressed. Subsequently, FN1 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 PBMCs 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 suggest strongly that Fli1 plays an important role in the pathogenesis of lupus. Furthermore, our preliminary studies indicate that Fli1 is over-expressed specifically in CD8+ T lymphocytes in MRL/lpr mice and that a polymorphism located in the promoter region of Fli1 affects its expression in a T cell line. We hypothesize that elevated levels of Fli1 in CD8+ T lymphocytes alter their proliferation, survival and/or function, specifically suppressor function, through the dysregulation of Fli1 target gene expression. The analysis of genes and gene products that regulate the immune system is central to understanding autoimmunity and research shows that FN1 clearly has effects on the immune system. Therefore, understanding the effects of over-expressing Fli1 and its transcriptional regulation in normal lymphocytes is necessary before we can begin to analyze and understand its dysregulation and role in lupus disease. Our long-term goal is to design methods to down-regulate Fli1 and identify other factors in the FN1 regulatory pathway as potential therapeutic targets in the treatment for human lupus. Currently, little is known regarding what role Fli1 plays in lymphocyte function or how FH1 gene expression is regulated in lymphocytes. To test our hypothesis and to lay the groundwork for our long-term goal, we propose to study the function and regulation of Fli1 in CD8+ T lymphocytes. Specifically, we propose the following: 1) Determine the molecular and phenotypic effects of over-expressing Fli1 in CD8+ T lymphocytes. To isolate the effects due solely to FN1 over-expression, we will analyze the molecular and phenotypic effects in CD8+ T lymphocytes isolated from control mice in which we over-express Fli1. 2) Identify mechanisms involved in the transcriptional regulation of Fli1 gene expression in CD8+ T lymphocytes. The major objective of these studies is to identify the trans-acting factors involved in the regulation of Fli1 expression in splenic CD8+ T lymphocytes. Results from these studies will be the foundation for future studies aimed at developing therapies for treating lupus patients.

描述（由申请人提供）： 狼疮小鼠模型MRL/LPR发展出早期发作自身免疫性疾病，显示出 与大多数死于肾衰竭的小鼠在人SLE中观察到的发病机制相似。正常小鼠 开发一种自身免疫性肾脏疾病，类似于在狼疮俯卧的小鼠模型中观察到的，在该模型中，ETS转录因子FLI1过度表达了。随后，显示FN1在容易发生NZB/NZB/NZW F1小鼠菌株的脾脏T细胞中表达过表达，狼疮prolone MRL/LPR小鼠的脾脏和SLE患者的PBMC。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在狼疮的发病机理中起重要作用。此外，我们的初步研究表明，在MRL/LPR小鼠中，FLI1在CD8+ T淋巴细胞中特别表达过表达，并且位于FLI1启动子区域中的多态性会影响其在T细胞系中的表达。 我们假设CD8+ T淋巴细胞中FLI1的水平升高改变了它们通过FLI1靶基因表达的失调，改变了它们的增殖，生存和/或功能，特别是抑制器功能。调节免疫系统的基因和基因产物的分析对于理解自身免疫性和研究表明，FN1显然对免疫系统有影响。因此，在我们开始分析和理解其功能障碍和在狼疮疾病中的作用之前，必须了解过表达FLI1及其在正常淋巴细胞中其转录调节的影响。我们的长期目标是设计下调节FLI1并确定FN1调节途径中其他因素的方法，作为人类狼疮治疗的潜在治疗靶标。当前，关于FLI1在淋巴细胞功能中的作用或如何调节淋巴细胞中FH1基因表达的作用鲜为人知。为了检验我们的假设并为我们的长期目标奠定基础，我们建议研究CD8+ T淋巴细胞中FLI1的功能和调节。具体而言，我们提出以下建议：1）确定过表达FLI1在CD8+ T淋巴细胞中的分子和表型效应。为了隔离仅由于FN1的过表达，我们将分析从过度表达FLI1的对照小鼠中分离出的CD8+ T淋巴细胞中的分子和表型效应。 2）确定涉及的机制 CD8+ T淋巴细胞中FLI1基因表达的转录调节。这些研究的主要目的是确定脾脏CD8+ T淋巴细胞中FLI1表达的调节所涉及的跨作用因子。这些研究的结果将是未来研究的基础，旨在开发用于治疗狼疮患者的疗法。