Significance of differentially expressed microRNAs and their target proteins in the development of autoimmune myocarditis in mouse model and patients
Final Report Abstract
The exact reasons why autoimmune myocarditis occurs in both patients and mice are still unknown. It has been observed that certain mouse strains, such as A/J and BALB/C, are prone to develop experimental autoimmune myocarditis (EAM), while others, such as strain BL/6, are not. In previous studies, we have found that regulation of differentially expressed microRNAs (miRs) may play an essential role. Therefore, we aim to develop new therapeutic approaches for patients in the long term by deepening our understanding of the mechanisms involved in susceptibility to EAM. In the context, we initially examined the role of miRs, specifically miR-34a and miR-135a, which are upregulated in BL/6 mice, in protecting against the onset of autoimmune myocarditis. Therefore, we tested whether inhibiting these miRs in BL/6 mice leads to the loss of resistance to EAM. Furthermore, we investigated whether enhanced expression of these miRs in the hearts of A/J mice using AAV9 vectors can protect against the development of an EAM. Additionally, we aimed to characterize the role of the target proteins of these miRs, including the miR-34a target protein PNUTS, in predisposition to autoimmune myocarditis. Then, we examined miR expression profiles within a mouse strain to understand why some mice do not develop myocarditis despite successful immunization. For animals with myocarditis in which miR-21a or miR-146b were upregulated, these miRs were inhibited to achieve a reduction or inhibition of inflammation and additional signaling pathways were analyzed. Furthermore, we investigated whether AAV9-mediated overexpression of these miRs can worsen the outcome of an EAM and analysed downstream signaling (e.g. IRAK1, TRAF6, ERK1/2, Sprouty1). Finally, we correlated the miR expression profile of myocarditis patients (blood samples, myocardial biopsies) with the miR expression profile of predisposed mice after TnI immunization.
