# Integrating Transcriptome Reprogramming Into Cardiac Plasticity Regulatory Mechanisms

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $610,124

## Abstract

PROJECT SUMMARY
Nearly every stressor reactivates the fetal gene program in cardiac myocytes, but why they make this transition
is unclear given fetal metabolic and functional reprogramming is insufficient to sustain adult cardiac performance
yet this fate change negatively impacts cardiac regeneration, which is an underlying determinant of heart failure.
Thus, understanding fetal to adult myocyte state transitions is has broad therapeutic impact when considering
how to boost the heart’s performance and tolerance for pathologic stress. A potent regulator of fetal to adult state
transitions and the switch from hyperplastic to hypertrophic growth in the postnatal heart is an RNA binding
protein causal for myotonic dystrophy (DM), Muscleblind-like 1 (MBNL1). Mosaic MBNL1 deficiency was newly
identified in the myocyte population following 2 weeks of pressure overload. Interestingly, only the MBNL1
deficient myocytes reactivated the fetal gene program, suggesting MBNL1 might regulate this switch during
cardiac stress. Indeed experimentally-derived MBNL1 deficiency in nearly every myocyte prevented pressure
overload-induced hypertrophic remodeling, but these hearts rapidly decompensated which we ascribe to their
inability to divide or hypertrophy. By contrast MBNL1 overexpression in pressure overloaded hearts prevented
fetal gene reprogramming and increases hypertrophic growth broadly across the myocyte population.
Collectively these data suggest a model whereby MBNL1 appears to regulate the optimal distribution of fetal
versus adult myocytes states needed to preserve cardiac performance in response stress and MBNL1-driven
deviations in those distributions determine the nature and severity of maladaptive remodeling. Hence this
application will test this hypothetical model by [1] examining the contribution of mosaic MBNL1 deficiency to the
nature and severity of cardiac remodeling in response to pathologic and physiologic increases in workload, [2]
determining the effects of maintaining MBNL1 expression in myocytes on cardiac remodeling, and [3] comparing
the effects of human mosaic MBNL1 deficiency from genetic deletion or DM on engineered cardiac tissue growth,
maturation, and performance in response to afterload.

## Key facts

- **NIH application ID:** 10879427
- **Project number:** 2R01HL141187-06
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jennifer Michelle Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $610,124
- **Award type:** 2
- **Project period:** 2018-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879427

## Citation

> US National Institutes of Health, RePORTER application 10879427, Integrating Transcriptome Reprogramming Into Cardiac Plasticity Regulatory Mechanisms (2R01HL141187-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879427. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*