Estudio del papel de los miRNA en el envejecimiento cardíaco
The functional deterioration suffered by the heart during aging is one of the main risk factors that determine the appearance of aging-associated pathologies which are a widespread cause of death. The left ventricle (LV) suffers serious diseases, however, it is the part of the heart less well studied at the molecular and functional level in humans, since donor samples are a limiting factor. The search for new therapies to prevent the effects of cardiac aging constitutes an essential point to fight against this global burden.
The hypothesis of one of the BSICoS group’s research lines is that microRNAs, small non-coding RNAs that negatively regulate gene expression, control transcriptional alterations related to the biological aging in the LV and, therefore, might be relevant therapeutic targets, even non-invasive biomarkers, of patients with advanced biological age. In a previous work, the group performed an analysis of the human left ventricle transcriptome and established a gene regulation network controlled by BIO-AGEmiRNA (miRNAs associated with biological aging). The objective of my master thesis is to select genes highly relevant for cardiac functions within the network, and then experimentally validate in vitro their predicted interaction with BIO-AGEmiRNA by using a luciferase reporter activity assay.
As result, twelve genes of interest (GOIs), predicted targets of miR24-2 and miR-4435, were selected and ten of them were successfully cloned into the reporter vector. The in vitro tests revealed six positive interactions: ADRA1A, ACTN2, SERCA2A, POPDC2 and TMOD1 with miR-24-2 and one, DSP, with miR-4435. The high percentage of validated interactions supports the network robustness and demonstrates that a single miRNA can regulate several genes involved in the contractile, structural or electrophysiological function of the human myocardium, among others. Therefore, and according to the initial hypothesis, the results demonstrate a direct interaction of BIO-AGEmiRNAs with the selected GOIs and highlight their potential value as a therapeutic target to regulate multiple deteriorated processes throughout human cardiac aging.