# Metabolic regulation of heart formation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The major obstacle to the successful application of human cardiac stem cell biology is the immaturity of in vitro stem
cell-derived cardiomyocytes. Genetic manipulations of stem cell-derived cardiomyocytes have not been successful in
achieving the maturity sufficient for regenerative medicine, drug screening, disease modeling and developmental
biology. Recent multi-center study revealed the importance of non-genetic contributors to the development of
congenital heart disease. Thus, in both in vitro and in vivo settings, non-genetic factors are understudied area of
research that can, combined together with the wealth of knowledge in genetic contributors to cardiogenesis, potentially
solve the immaturity issue of stem cell-derived cardiomyocytes. In fact, the metabolic/nutritional environment is a
major non-genetic factor that impact heart formation. It is well-established that maternal hyperglycemia is associated
with significant increase in the risk of congenital heart disease. However, little is known about whether high glucose
directly impact the differentiation of cardiomyocytes and how high glucose might impact the flow of downstream
metabolic pathways. Glucose is the most critical nutrients to the cells and its metabolism is tightly regulated in any
cells. In the fetal heart, glucose is taken up through transporter isoforms 1 and 4 and processed through multiple
catabolic and anabolic pathways including glycolysis, TCA, pentose phosphate pathway, hexosamine pathway, etc.
Our preliminary data with human embryonic stem cell-derived cardiomyocytes and murine model of diabetic
pregnancy suggest that it is not the catabolic extraction of energy but the anabolic biosynthesis of nucleotides from
glucose that plays a major role in regulating cardiogenesis during fetal stage. These results have led to our central
hypothesis that glucose inhibits fetal cardiac maturation via nucleotide biosynthesis. This proposal will test it by
genetic, metabolic, and physiological analyses in vivo and in vitro. The results are expected to demonstrate that unique
metabolic environment of fetal heart is not merely a consequence of genetic differentiation program but also a driver
of cardiac maturation. By focusing on understudied area of cardiogenesis research, this study will add another
dimension to our understanding of cardiogenesis and congenital heart disease.

## Key facts

- **NIH application ID:** 9933992
- **Project number:** 5R01HL142801-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Atsushi Nakano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933992

## Citation

> US National Institutes of Health, RePORTER application 9933992, Metabolic regulation of heart formation (5R01HL142801-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9933992. Licensed CC0.

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