Characterization of microRNA-regulated signaling pathways in mouse SLE

描述（由申请人提供）：系统性红斑狼疮（SLE，狼疮）是一种慢性全身性自身免疫性疾病，其特征是B细胞和T细胞的自身反应性，自身抗体的产生和免疫复合物的组织沉积，导致器官损伤。狼疮患者的免疫调节紊乱与狼疮易感基因有关。B细胞的过度活跃和异常反应是SLE发病的核心，并导致自身抗体的产生增加、自身耐受机制的失败和免疫复合物的清除不足。microRNAs （miRNAs）在过去十年中作为一类保守的非编码rna出现，它调节基因表达。越来越多的证据强调了这一途径的重要性，其触手控制着发育、正常生理过程和疾病状态中的调节回路。目前的证据支持mirna在免疫系统的发育和功能中发挥关键作用，新出现的证据强调了这种调节途径在自身免疫中的重要性。然而，在SLE中由mirna调节的信号通路在很大程度上仍然未知。本实验室主要研究mirna在三基因小鼠模型B6.Sle123中的功能。B6的自身免疫性疾病Sle123的特点是自身抗体、淋巴脾肿大和肾小球肾炎，与人类狼疮非常相似。我们研究了mirna在B6中的表达。Sle123淋巴细胞，在12个月内的不同时间点，而自身免疫性疾病的B6。Sle123小鼠从轻度发展到重度。我们证明了一组mirna的表达与严重狼疮表现（如肾脏疾病）的发展和严重程度呈正相关。目前可用于SLE的治疗方法是有毒的，它们不是针对狼疮特异性紊乱机制。拟议的研究重点是鉴定在狼疮小鼠模型中受独特影响的mirna依赖性信号通路，狼疮小鼠模型的疾病表现和紊乱机制与人类狼疮重叠。在我们的研究中，我们将采用新颖的体内实验方法结合标准的体外技术。我们的最终计划是扩大我们对狼疮中miRNA功能的认识和理解，并确定狼疮中潜在的新治疗靶点。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by auto reactivity of B and T cells, production of autoantibodies and tissue deposition of immune complexes, resulting in organ damage. Disordered immunoregulation in SLE occurs in a genetic background involving lupus susceptibility genes. Hyperactivity and abnormal responses of B cells is at the center of SLE pathogenesis and leads to increased production of autoantibodies, failure of self tolerance mechanisms and inadequate clearing of immune complexes. microRNAs (miRNAs) emerged over the last decade as a conserved class of non-coding RNAs that regulates gene expression. Accumulating evidence underscores the importance of this pathway, whose tentacles control regulatory circuits in development, in normal physiologic processes and in disease state. Current evidence supports a key role for miRNAs in the development and function of the immune system and emerging evidence underscores the importance of this regulatory pathway in autoimmunity. However, the signaling pathways regulated by miRNAs in SLE remain largely unknown. Research in our lab focuses on the function of miRNAs in the tri-congenic mouse model B6.Sle123. Autoimmune disease in B6.Sle123 is characterized by autoantibodies, lymphosplenomegaly and glomerulonephritis, strongly resembling human lupus. We studied the expression of miRNAs in B6.Sle123 lymphocytes, at different time points in the course of twelve months, while the autoimmune disease of B6.Sle123 mice progresses from mild to severe. We demonstrated that expression of a set of miRNAs positively correlates with development and severity of severe lupus manifestations, such as kidney disease. Current therapies available for SLE are toxic and they are not targeting lupus-specific disordered mechanisms. The proposed research focuses on identifying miRNA-dependent signaling pathways that are uniquely affected in a mouse model of lupus, in which disease manifestations and disordered mechanisms overlap with those in human SLE. In our studies we will employ novel in vivo experimental methods combined with standard in vitro techniques. Our ultimate plan is to broaden our knowledge and understanding of miRNA function in lupus and to identify potential novel therapeutic targets in SLE. PUBLIC HEALTH RELEVANCE: Results from basic, translational and clinical research underscore the importance of gene regulation mediated by microRNAs (miRNAs). miRNAs control pathways important in normal development and normal cellular functions, however they also play instrumental roles in disease mechanisms. Although current evidence supports a critical role for miRNAs in the development and function of the immune system, very little is known about the function of miRNAs in autoimmune diseases and in particular in Systemic Lupus Erythematosus (SLE). We propose to identify and characterize the molecular pathways that are regulated by miRNAs in lupus, using a genetic tricongenic mouse lupus model that recapitulates many seroligcal and clinical manifestations of human disease. Our long term goal is to identify disordered molecular pathways in lupus, which could potentially serve as novel, disease specific, therapeutic targets. We foresee that results of the studies described in this proposal will be of considerable interest to a broad spectrum of biomedical disciplines