microRNA Control of Dilated Cardiomyopathy Dilated cardiomyopathy is a major cause of heart failure and approximately 20-35% of cases have genetic etiologies. The link between the genetics and disease progression remains poorly understood, despite being a major focus of current research. microRNAs have emerged as important regulators of heart disease. Approximately 2000 of these short, non-coding RNA molecules function in vivo by repressing the stability and translation of protein-coding mRNAs. miRNAs regulate nearly all biological processes examined, often by suppressing multiple points in a pathway produce a coherent biological response to stimuli. We have recently used functional screening of whole genome collections of synthetic miRNAs to identify miRNAs that suppress cardiomyocyte contractility in vitro and shown that blocking one of these, miR-25, improves heart function in a heart failure model (Nature, 2014, doi:10.1038). We applied high throughput screening to identify miRNAs that regulate the decline in cardiomyocyte function in familial DCM using patient-specific hiPSCs. Mechanical strain and chronic adrenergic stimulation induce a number of these miRNAs. Together our data have revealed that miRNAs connect physiological stress to suppression of proteins that maintain calcium regulation and sarcomeric integrity. Here we propose to systematically investigate miRNA control of familial DCM.
AIMS 1 and 2 will identify miRNAs that have the potential to suppress contractility in DCM, using patient hiPSC-cardiomyocytes (cTn-T R173W and R141W) and a mouse DCM model corresponding to one of the DCM patient hiPSC models (cTn-T R173W);
AIM 3 will determine the proteins that are repressed by the miRNAs to influence disease, and AIM 4 will establish how miRNAs midiate the response to pathological stimuli of increased wall tension and chronic adrenergic stimulation that contribute to disease progression. In summary, the research addresses the hypothesis that familial DCM involves dysregulation of miRNAs that impair Ca2+ handling, contractility and sarcomere integrity. Elucidating the miRNAs and their protein targets should provide insight into disease progression and point to novel therapeutic targets.

Public Health Relevance

microRNA Control of Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the third most prevalent cause of heart failure, which continues to be the major cause of death in the US. There is only rudimentary understanding of the link between the genetic causes and the disease itself, and only a few pharmacological approaches to its treatment. Here we will apply high throughput screening technology to discover microRNAs and proteins that control the decline in heart function in DCM, with the goal of understanding the disease and revealing candidate drug targets for its treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130840-03
Application #
9492603
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2016-06-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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