This proposal describes a five-year career development program to prepare the candidate, Dr. Sushma Reddy, for a career as an independent scientist evaluating the mechanisms of right heart failure. This program will expand Dr. Reddy's scientific background in cardiovascular research by providing technical training and expertise in myocardial, mitochondrial and endothelial biology through focused course work, technical training and targeted externships. In addition, Dr. Reddy's successful transition from a mentored clinician scientist to an independent scientist will be accomplished by strengthening skills in critical thinking, communication, collaboration, mentorship and laboratory management. MicroRNAs (miRs) are small non-coding RNAs that have emerged as crucial regulators of cardiac remodeling. However, there is minimal data on their role in right ventricular hypertrophy (RVH) and failure (RVF). Understanding the mechanisms of RV remodeling is a critical question for many patients with congenital heart disease, given that the afterload stressed RV is more likely to fail compared to the left ventricle (LV), and that standard heart failure therapies fail o work in patients with RVF. Although the molecular responses of the RV and LV to pressure overload are largely similar, there are key differences in regulators of oxidant stress and angiogenesis which could explain the enhanced vulnerability of the RV. Dr. Reddy's objective is to elucidate the role of miRs as a mechanism for these RV-LV differences. Using a murine model, she has identified miRs 34a, 28, 93 and 148a as unique to RVH/RVF. Of interest, all four miRs are expressed only in non-cardiomyocytes yet may have their greatest effects in cardiomyocytes. She hypothesizes that RV-specific non-cardiomyocyte miR-34a, through crosstalk with cardiomyocytes, is responsible for the early failure of antioxidant defenses and the attenuated angiogenic response in RVF.
Aim 1 will evaluate the mechanisms by which miR-34a regulates the transition from RVH to RVF. Overexpression of miR-34a in fibroblasts, endothelial cells and cardiomyocytes will evaluate effects on ROS production, antioxidant defenses, and mediators of cell death and angiogenesis, as well as the mechanism of miR-34a crosstalk with cardiomyocytes and the paracrine role of exosomes.
Aim 2 will evaluate the in vivo functional significance of miR-34a using LNA antimiRs to rescue RVF in her murine model, identify novel target genes using transcriptome and RISCome sequencing, and identify plasma biomarkers of disease progression in children with RVH/RVF. Future studies will evaluate (i) the mechanism of action of miRs 28, 93 and 148a, either singly or in concert in the RV susceptibility to heart failure; (ii) the role of these miRs in a model of chronic pressure overload and (iii) validate plasma biomarkers in a larger cohort of children. In summary, these studies will aid in developing RV-specific heart failure therapies and identify biomarkers of RV failure, allowing earlier medical or surgical intervention.
Right ventricular hypertrophy (RVH) and the transition to RV failure (RVF) is a critical question for many patients with congenital heart disease, given that th afterload stressed RV is more likely to fail compared to the left ventricle (LV), and that standard heart failure therapies fail to work in these patients. My objective is to elucidate the role of mis as a mechanism for these RV-LV differences, to identify potential biomarkers of the progression from RVH to RVF as well as RV-specific therapeutic targets.
| Reddy, Sushma; Bernstein, Daniel; Newburger, Jane W (2018) Renin-Angiotensin-Aldosterone System Inhibitors for Right Ventricular Dysfunction in Tetralogy of Fallot: Quo Vadis? Circulation 137:1472-1474 |
| Reddy, Sushma; Bernstein, Daniel (2015) The vulnerable right ventricle. Curr Opin Pediatr 27:563-8 |
