# Cardiac Circadian Clock and Dilated Cardiomyopathy

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $480,000

## Abstract

Project Summary/Abstract
Rev-erbα/β are druggable components of the molecular circadian clock. How cardiac Rev-erb regulates heart
function has not been studied in vivo. We generated a cardiomyocyte-specific Rev-erbα/β double knockout (Rev-
CKO) mouse model. Rev-CKO mice display progressive dilated cardiomyopathy that leads to heart failure and
complete lethality. In adult Rev-CKO mice, inducible cardiomyocyte-specific re-expression of Rev-erbα that is
in-phase, but not anti-phase, with its endogenous oscillation pattern rescued contractile defects and heart failure,
demonstrating the importance of the Rev-erb oscillation per se in cardiac functions. RNA-seq, ChIP-seq,
metabolomics, and metabolic tracer studies revealed profound alterations in mitochondrial oxidative metabolism
in the Rev-CKO heart, particularly at night. We hypothesize that Rev-erb regulates heart function through
temporal coordination of anticipatory expression of metabolic genes and the diurnal lipid availability to the
myocardium. We will determine how cardiac Rev-erb regulates gene expression oscillation and how the
oscillation affects cardiac functions; delineate the molecular mechanism underlying cardiac Rev-erb-mediated
gene expression regulation; explore how cardiac Rev-erb regulates myocardial metabolism; and characterize
Rev-erb agonist in treating dilated cardiomyopathy. Using a new mouse model, a novel phase-restricted re-
expression technique, and integrative multi-omics approaches, we aim to provide new insights into how the
circadian clock regulates gene expression and “housekeeping” functions such as energy metabolism in
cardiomyocytes in the pathobiology of heart failure, which can potentially lay an intellectual groundwork for novel
chronotherapy strategies of dilated cardiomyopathy.

## Key facts

- **NIH application ID:** 10033596
- **Project number:** 1R01HL153320-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zheng Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,000
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033596

## Citation

> US National Institutes of Health, RePORTER application 10033596, Cardiac Circadian Clock and Dilated Cardiomyopathy (1R01HL153320-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033596. Licensed CC0.

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