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，lupus）是一种慢性全身性自身免疫性疾病，其特征是B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。SLE免疫调节紊乱发生在涉及狼疮易感基因的遗传背景中。B细胞的过度活跃和异常反应是SLE发病机制的中心，并导致自身抗体产生增加、自身耐受机制失效和免疫复合物清除不足。 microRNA（miRNAs）是近十年来发现的一类调控基因表达的保守的非编码RNA。 越来越多的证据强调了这一途径的重要性，它的触角控制着发育、正常生理过程和疾病状态中的调节回路。目前的证据支持miRNAs在免疫系统的发育和功能中的关键作用，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miRNAs调控的信号通路在很大程度上仍然未知。 本实验室的研究主要集中在miRNAs在三同源小鼠模型B6.Sle123中的功能。B6.Sle123的自身免疫性疾病以自身抗体、淋巴脾肿大和肾小球肾炎为特征，与人类狼疮非常相似。我们研究了B6.Sle123小鼠自身免疫性疾病从轻度进展到重度的过程中，在12个月的过程中的不同时间点，B6.Sle123淋巴细胞中的miRNA表达。我们证明了一组miRNAs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的治疗是有毒的，并且它们不针对狼疮特异性紊乱机制。拟议的研究重点是确定在狼疮小鼠模型中受到独特影响的miRNA依赖性信号通路，其中疾病表现和紊乱机制与人类SLE重叠。在我们的研究中，我们将采用新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功能的知识和理解，并确定SLE的潜在新治疗靶点。

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.