Role of the transcription factor ARID3a in lupus

转录因子 ARID3a 在狼疮中的作用

• 批准号: 8074998
• 负责人: Carol F Webb
• 金额: $ 20.17万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-24 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074998
• 关键词: Address; Adult; Affect; Age; Antibodies; Autoantibodies; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Cell Count; Cell Lineage; Cell physiology; Cells; Characteristics; DNA Sequence; DNA-Binding Proteins; Data; Defect; Deposition; Development; Disease; Epigenetic Process; Etiology; Exhibits; Flow Cytometry; Future; Gene Expression; Genetic Transcription; Goals; Heavy-Chain Immunoglobulins; Human; Immune response; Immunoglobulins; Individual; Kidney; Kidney Glomerulus; Lead; Link; Lupus; Mature B-Lymphocyte; Membrane; Mus; Nuclear Antigens; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Production; Protein Family; Proteins; Publishing; Research; Role; Sampling; Signal Transduction; Stem cells; Subgroup; Surface Immunoglobulins; Symptoms; Systemic Lupus Erythematosus; Time; Transgenic Mice; Treatment Protocols; base; immunoglobulin receptor; insight; member; peripheral blood; protein complex; public health relevance; receptor; research study; response; transcription factor; treatment response

DESCRIPTION (provided by applicant): The goal primary of this study is to determine if over-expression of the transcription factor ARID3a in a subset of systemic lupus erythematosus patients is a contributing factor to this disease. We previously showed that over-expression of the mouse orthologue of ARID3a in B lineage cells results in breaches of B cell tolerance. The over-expressing transgenic mice produce anti-nuclear antigen antibodies (a defining characteristic of lupus) by four weeks of age, accumulate immunoglobulin deposits in kidney glomeruli and exhibit shifts in numbers of peripheral blood B cell subsets. Our preliminary data indicate that ARID3a is aberrantly over-expressed in a large subset of lupus patients, but not in healthy age-matched individuals. We hypothesize that patients with aberrant expression may constitute a new subgroup of patients with similar underlying defects. Furthermore, we hypothesize that ARID3a over-expression facilitates disease development. Three specific aims are proposed. First, we will determine if aberrant ARID3a expression is a stable characteristic of some patients, or if over-expression occurs as the result of drug treatment or immune response over time. Secondly, we will determine how aberrant ARID3a expression affects B cell functions which may pertain directly to breaches in B cell tolerance. Finally, we will identify the specific mechanisms which contribute to aberrant ARID3a expression in these cells. These data will provide the basis for directing future studies to determine how ARID3a contributes to autoimmunity. The ability to group patients by specific symptoms and to understand the underlying mechanisms which contribute to lupus could lead to better treatment regimens. PUBLIC HEALTH RELEVANCE: Our published data indicate that over-expression of the transcription factor ARID3a/Bright in transgenic mouse B cells results in production of autoimmune antibodies. Preliminary new data suggest that ARID3a is inappropriately expressed in a subset of lupus patients. The goal of this study is to determine if how inappropriate ARID3a expression contributes to lupus pathogenesis.

描述（由申请人提供）：本研究的主要目标是确定转录因子 ARID3a 在系统性红斑狼疮患者亚群中的过度表达是否是导致该疾病的一个因素。我们之前表明，B 谱系细胞中 ARID3a 的小鼠直系同源物的过度表达会导致 B 细胞耐受性的破坏。过度表达的转基因小鼠在四周龄时产生抗核抗原抗体（狼疮的一个定义特征），在肾小球中积累免疫球蛋白沉积物，并表现出外周血 B 细胞亚群数量的变化。我们的初步数据表明，ARID3a 在大部分狼疮患者中异常过度表达，但在健康年龄匹配的个体中却没有异常过度表达。我们假设表达异常的患者可能构成具有相似潜在缺陷的新患者亚组。此外，我们假设 ARID3a 过度表达会促进疾病的发展。提出了三个具体目标。首先，我们将确定异常的 ARID3a 表达是否是某些患者的稳定特征，或者随着时间的推移，药物治疗或免疫反应是否会导致过度表达。其次，我们将确定异常的 ARID3a 表达如何影响 B 细胞功能，这可能与 B 细胞耐受性的破坏直接相关。最后，我们将确定导致这些细胞中 ARID3a 表达异常的具体机制。这些数据将为指导未来的研究奠定基础，以确定 ARID3a 如何促进自身免疫。根据特定症状对患者进行分组并了解导致狼疮的潜在机制的能力可能会导致更好的治疗方案。 公共健康相关性：我们发表的数据表明，转基因小鼠 B 细胞中转录因子 ARID3a/Bright 的过度表达会导致自身免疫抗体的产生。初步的新数据表明 ARID3a 在狼疮患者的亚群中表达不当。本研究的目的是确定 ARID3a 表达不当是否会导致狼疮发病机制。