Significance of differentially expressed microRNAs and their target proteins in the development of autoimmune myocarditis in mouse model and patients

差异表达的microRNA及其靶蛋白在小鼠模型和患者自身免疫性心肌炎发生中的意义

• 批准号: 284027736
• 负责人: Professor Dr. Ziya Kaya
• 金额: --
• 依托单位: Institut für Molekulare und Translationale Therapiestrategien
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284027736?language=en
• 关键词: Significance; differentially; expressed; microRNAs; their

Causes for a predisposition for an autoimmune myocarditis in patients as well as animals are still unknown. It has been shown that some mouse strains (A/J and BALB/C) are susceptible to the induction of an experimental autoimmune myocarditis and some are not (C57BL/6). In preliminary studies, we could identify a potential involvement of differentially expressed microRNA (miRs), small non-coding oligoribonucleotides, in the predisposition for an autoimmune myocarditis. The aim of our study is to elucidate the mechanisms involved in the different susceptibility to an autoimmune myocarditis and identify novel therapeutic targets. In this study, we will analyze the role of miRs upregulated in the C57BL/6 strain. Since miR-34a-5p and miR-135a-5p appear to be protective in these mice we will study how inhibiting these miRs in C57BL/6 mice affect the susceptibility to autoimmune myocarditis. Furthermore, we will analyze if the overexpression of these miRs via AAV9-vectors in the hearts of A/J- as well as BALB/C-mice will be protective. Finally, the role of target proteins of these miRs such as PNUTS in the disposition for an autoimmune myocarditis will be evaluated. In a further approach, we will investigate if treating animals with miR inhibitors against miRs upregulated in our model of autoimmune myocarditis such as miR-21a-5p or miR-146b-5p will reduce or inhibit an inflammation. Moreover, novel signaling pathways associated with these miRs will be investigated. In particular, we will analyze if the overexpression of selected target proteins (e.g. IRAK1, TRAF6, ERK1/2, Sprouty 1) with AAV9-vectors will be able to prevent an EAM. In a last step, we will investigate if the miR-expression profile of susceptible mice after TnI immunization correlates with the miR-expression profils of patients analyzed in blood samples and heart biopsies. These analyses should enable novel insights in the susceptibility to autoimmune myocarditis in humans and result in identification of novel therapeutic targets.

在患者和动物中易患自身免疫性心肌炎的原因仍然未知。已表明，一些小鼠品系（A/J和BALB/C）对诱导实验性自身免疫性心肌炎敏感，而一些小鼠品系（C57 BL/6）则不敏感。在初步研究中，我们可以确定差异表达的microRNA（miR），小的非编码寡核苷酸，在自身免疫性心肌炎的易感性的潜在参与。本研究的目的是阐明自身免疫性心肌炎易感性不同的机制，并确定新的治疗靶点。在这项研究中，我们将分析C57 BL/6菌株中miR上调的作用。由于miR-34 a-5 p和miR-135 a-5 p在这些小鼠中似乎具有保护作用，我们将研究在C57 BL/6小鼠中抑制这些miR如何影响对自身免疫性心肌炎的易感性。此外，我们将分析这些miR通过AAV 9载体在A/J-以及BALB/C-小鼠心脏中的过表达是否具有保护性。最后，将评估这些miR的靶蛋白如PNUTS在自身免疫性心肌炎的处置中的作用。在进一步的方法中，我们将研究用针对在我们的自身免疫性心肌炎模型中上调的miR（例如miR-21 a-5 p或miR-146 b-5 p）的miR抑制剂治疗动物是否会减少或抑制炎症。此外，与这些miR相关的新的信号通路将被研究。特别地，我们将分析用AAV 9载体过表达选定的靶蛋白（例如IRAK 1，TRAF 6，ERK 1/2，Sprouty 1）是否能够预防EAM。在最后一步中，我们将研究TnI免疫后易感小鼠的miR表达谱是否与血液样本和心脏活检中分析的患者的miR表达谱相关。这些分析应该能够对人类自身免疫性心肌炎的易感性有新的见解，并导致新的治疗靶点的鉴定。