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

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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.