Molecular characterization of a novel miRNA: miR-1954 in cardiac remodeling

Project: Research

Investigators

  • Sudhiranjan Gupta (PI)

Description

Cardiac remodeling is a major cause for morbidity and mortality in humans and stands as a serious health issue. The process involves structural, morphological and functional changes including cardiac hypertrophy, apoptosis, interstitial fibrosis, etc. leading to cardiac dysfunction. The cellular responses of cardiomyocytes (CM) and cardiac fibroblasts (CF) are delicately regulated to maintain homeostasis and prevent cardiac remodeling. Recently, microRNAs (miRNAs) have emerged as a new class of post-transcriptional regulators having a key role in cardiac pathologies, but the mechanism underlying the miRNAs' function in cardiac remodeling remains unknown. Using next generation sequencing analysis, we have discovered a set of novel dysregulated miRNAs. Among them one was identified as miR-1954 which was significantly reduced under thoracic aortic constricted (TAC) and Angiotensin II infusion in wild-type mice. Our central hypothesis is that deficiency of miR-1954 promotes adverse cardiac remodeling leading to hypertrophy and fibrosis via cellular cross-talk; and overexpression of miR-1954 mitigates the cardiac damage and abrogates the adverse remodeling by modulating Sp1-Gata4-Col I-Tsp1-axis. Our Specific Aims (SA) in this proposal is: (1) Test the hypothesis that deficiency of miR-1954 promotes cardiac cells remodeling through a paracrine mechanism, in vitro. This SA will define the mechanism of mi-1954-mediated regulation of Sp1-Gata4-Col I-Tsp1-axis in cardiac cells. We will perform mRNA and miRNA expression profiling, determine the key patterns of cardiac remodeling, (CM hypertrophy, apoptosis, CF proliferation and myofibroblasts differentiation) by high throughput qRT PCR followed by validation at protein level. (2) Determine the underlying novel mechanism of miR-1954 dysregulation by experimentally-induced cardiac remodeling, in vivo. This SA will delineate the mechanism and function of miR-1954 in cardiac remodeling using WT and miR-1954 Tg mice followed by TAC and Ang II-infusion. This specific aim is also investigating the cause and effect relationship of miR-1954 and cardiac remodeling, in vivo. This SA will determine the therapeutic efficacy of miR-1954 in cardiac remodeling using unconjugated locked nucleic acid (LNA) of anti-miR-1954 and mimic of miR-1954. The mRNA/miRNA expressions, the key patterns of cardiac remodeling, LV hemodynamics and LV function will be determined. Complementary studies will be implemented using human subjects. The tis
Award amount$154,000.00
Award date07/01/2017
Program typeGrant-in-Aid
Award ID17GRNT33670897
Effective start/end date07/01/201706/30/2019
StatusFinished