Characterization of Y-linked Autoimmune Accelerator Yaa

Y 连锁自身免疫加速器 Yaa 的表征

• 批准号: 7075012
• 负责人: Derry Charles Roopenian
• 金额: $ 25.2万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075012
• 关键词: B lymphocyte; autoimmunity; biological signal transduction; chromosome translocation; functional /structural genomics; gene expression; gene targeting; genetic regulation; genetic strain; genetic susceptibility; genetically modified animals; immunogenetics; laboratory mouse; phenotype; phosphoprotein phosphatase; sex linked trait; systemic lupus erythematosus; transfection

DESCRIPTION (provided by applicant): Susceptibility to systemic lupus erythematosus (SLE) has a genetic component, however, the complex genetic variation that results in risk for initiation and progression of this syndrome remains poorly understood. Mouse models for SLE continue to provide key insights into the genetic and phenotypic etiology of this complex disease syndrome. Among them, the BXSB.Yaa mouse model is intriguing both from a genetic and disease perspective. BXSB.Yaa male mice develop a quite severe autoimmune syndrome as a consequence of epistatic interactions between BXSB-background SLE-predisposition alleles and the Y-chromosome-linked autoimmune accelerator locus (Yaa). This ultimately results in severe autoimmunity, leading to death by acute renal failure. Yaa is, arguably, the most substantial SLE risk factor identified in mice, and also the most intractable. Yaa dramatically enhances overall autoimmune responses against autoantigens through its intrinsic effect on B-cell activation, presumably by decreasing the threshold for antigen receptor-dependent stimulation. Through a combination of genetic, genomic, transcriptional, and functional analyses, we have identified a very strong candidate gene for Yaa. Midline 1 (Midin) normally maps near the pseudoautosomal boundary of the X chromosome. Its protein is normally associated with cell proliferation and differentiation, has been shown to bind to the B-cell receptor associated signaling protein, Igbpl, and interacts with a rapamycin sensitive signaling pathway. We have found that this positive regulator of B-cell activation has been transferred from the X to the Y chromosome by an interchromosomal translocation event in male Yaa mice. This duplication, designated Midy, results in an overall elevation of Midin transcriptional expression in male Yaa mice. Our overall hypothesis is that the transposition of Midin onto the Yaa chromosome explains the Yaa phenotype. Mechanistically, we propose that the elevation of Midin expression caused by this translocation results in B-cell hyperactivity by decreasing phosphatase activity that normally represses action of a major cell kinase. We will (1) genomically characterize the structure of Midy, (2) determine the effect of transgenically elevated Midin expression on B-cell signaling and autoimmunity, and (3) inactivate Midy to evaluate its potential for generating the Yaa phenotype. These studies will clarify the molecular mechanisms by which Midin could impact B-cell signaling pathways generally leading to SLE pathogenesis both in mice and humans. Relevance to public health. SLE is one of the most challenging of all autoimmune disorders to predict and effectively treat. Mouse models can be used advantageously to understand how genetics influence this disease, to predict genetic predisposition, and to identify therapeutic targets. We have identified a key gene for mouse SLE. Understanding it will provide substantial insight into human SLE syndromes.

描述（由申请人提供）：系统性红斑狼疮（SLE）的易感性具有遗传成分，然而，导致该综合征发生和进展风险的复杂遗传变异仍知之甚少。 SLE的小鼠模型继续为这种复杂疾病综合征的遗传和表型病因学提供关键见解。 其中，BXSB.Yaa小鼠模型从遗传和疾病的角度都很有趣。 BXSB.Yaa雄性小鼠由于BXSB背景SLE易感等位基因和Y染色体连锁的自身免疫加速基因座（Yaa）之间的上位相互作用而发展出相当严重的自身免疫综合征。 这最终导致严重的自身免疫，导致急性肾衰竭死亡。 可以说，Yaa是在小鼠中确定的最重要的SLE风险因素，也是最难处理的。 Yaa通过其对B细胞活化的内在作用，可能是通过降低抗原受体依赖性刺激的阈值，显著增强针对自身抗原的整体自身免疫应答。 通过遗传、基因组、转录和功能分析的结合，我们已经确定了一个非常强的Yaa候选基因。 中线1（Midin）通常定位在X染色体的假常染色体边界附近。 其蛋白质通常与细胞增殖和分化相关，已显示与B细胞受体相关的信号传导蛋白Igbpl结合，并与雷帕霉素敏感的信号传导途径相互作用。 我们发现，这种B细胞激活的正调节因子已通过雄性Yaa小鼠的染色体间易位事件从X染色体转移到Y染色体。 这种重复，命名为Midy，导致雄性Yaa小鼠中Midin转录表达的总体升高。 我们的总体假设是Midin转座到Yaa染色体上解释了Yaa表型。 从机制上讲，我们认为这种易位引起的Midin表达的升高通过降低磷酸酶活性导致B细胞过度活跃，而磷酸酶活性通常抑制主要细胞激酶的作用。 我们将（1）从基因组学上表征Midy的结构，（2）确定转基因提高的Midin表达对B细胞信号传导和自身免疫的影响，以及（3）研究Midy以评估其产生Yaa表型的潜力。 这些研究将阐明Midin影响B细胞信号通路的分子机制，这些信号通路通常导致小鼠和人类SLE发病机制。 与公共卫生的相关性。 SLE是所有自身免疫性疾病中最具挑战性的预测和有效治疗的疾病之一。小鼠模型可以有利地用于了解遗传学如何影响这种疾病，预测遗传易感性，并确定治疗靶点。 我们已经确定了小鼠SLE的关键基因。 了解它将为人类SLE综合征提供实质性的见解。