Identification and characterization of long non-coding RNAs (lncRNAs) that modulate cardiac extracellular matrix

• Grant number: 21/08797-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2022
• End date: May 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: José Eduardo Krieger
• Grantee: Caio Mateus da Silva
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 14/50889-7 - National Institute of Science and Technology Medicine Assisted by Scientific Computing (INCT-MACC), AP.TEM
• Associated scholarship(s): 24/04572-3 - Role of Long Non-Coding RNAs (lncRNAs) in Cell-Cell Communication and Extracellular Matrix in Post-Myocardial Infarction, BE.EP.DR

Abstract

Cardiovascular ischemic diseases are one of the leading causes of mortality in the world. Cell death and tissue loss resulting from blood flow interruption trigger a repair process that replaces muscle with fibrotic tissue. In this process, the extracellular matrix (ECM) undergoes changes in its structure and composition. Recent studies suggest that the ECM may be a suitable target for cell therapies. Our group demonstrated that mesenchymal cell therapy is able to beneficially modify post-infarction heart matrix characteristics even after a month of its reorganization through possible paracrine, transient, and local effects. Despite the role of fibroblasts in extracellular matrix synthesis or degradation, these cells have received little attention as a target of paracrine action associated with cell therapy. In this context, we propose to evaluate long non-coding RNAs (lncRNAs) due to their role as regulatory elements of gene expression through its sponging effect of miRNAs or as endogenous competing RNAs (ceRNAs). We aim to use public databases from platforms such as microarrays, RNA-seq, and single-cell RNA-seq to build ceRNA networks and select lncRNAs within fibroblast populations that modulate ECM throughout the post-infarction period. The lncRNAs selected using the topological characteristics of the ceRNAs networks will be characterized in vitro using a decellularized matrix model derived from healthy or infarcted animal models. The matrices will be repopulated, and the effects of treatments on ECM structure and cell composition will be evaluated using antisense oligonucleotide silencing (AOs-GapmeRs), confocal microscopy, HCS, and gene expression. These studies will contribute to identifying new candidates associated with pleiotropic effects resulting from the beneficial outcome induced by cell therapies with multipotent cells after myocardial infarction.