Characterization of microRNA-regulated signaling pathways in mouse SLE

小鼠 SLE 中 microRNA 调节信号通路的表征

基本信息

批准号：
8847172
负责人：
MARIANTHI KIRIAKIDOU
金额：
$ 3.55万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847172
关键词：
Characterization microRNA regulated signaling pathways

项目摘要

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.

描述（由申请人提供）：全身性红斑狼疮（SLE，狼疮）是一种慢性全身自身免疫性疾病，其特征是B和T细胞的自动反应性，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中的免疫调节无序发生在涉及狼疮易感基因的遗传背景中。 B细胞的多动症和异常反应位于SLE发病机理的中心，导致自身抗体的产生增加，自耐受机制的失败以及免疫复合物的清除不足。在过去的十年中，microRNA（miRNA）是调节基因表达的一类无编码RNA。积累的证据强调了这一途径的重要性，该途径的触角在正常的生理过程和疾病状态下控制发育中的调节回路。当前的证据支持miRNA在免疫系统的发展和功能中的关键作用，而新兴证据则强调了这种监管途径在自身免疫性中的重要性。但是，SLE中miRNA调节的信号通路仍然很大未知。我们实验室中的研究重点是miRNA在三 - 综合小鼠模型B6.SLE123中的功能。 B6.SLE123中的自身免疫性疾病的特征是自身抗体，淋巴结瘤和肾小球肾炎，非常类似于人类狼疮。我们研究了MIRNA在B6.SLE123淋巴细胞中的表达，在十二个月的不同时间点，而B6.SLE123小鼠的自身免疫性疾病从轻度到重度发展。我们证明，一组miRNA的表达与严重的狼疮表现（例如肾脏疾病）的发育和严重程度正相关。当前可用于SLE的疗法有毒，它们没有针对狼疮特异性机制。拟议的研究重点是识别miRNA依赖性信号传导途径，这些信号通路在小鼠模型中受到唯一影响，其中疾病表现和机制与人SLE中的机制重叠。在我们的研究中，我们将采用新型的体内实验方法与标准体外技术结合。我们的最终计划是扩大对狼疮中miRNA功能的知识和理解，并确定SLE中潜在的新型治疗靶标。