# Nuclear-Metabolic Interplay in Down syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $676,644

## Abstract

Abstract
Down syndrome (DS) is a complex genetic disorder with significant physical, cognitive, and behavioral
manifestations. Individuals with DS are also more likely to develop certain health conditions including those
related to dysfunctional metabolism, such as obesity and diabetes. Further, converging lines of evidence suggest
that cellular metabolism is a critical regulator of neurodevelopment, and that metabolites play key roles in
regulating neural progenitor cell (NPC) proliferation fate specification required for proper brain development.
Despite this, studies have largely overlooked the influence of cellular metabolism on the neurodevelopmental
deficits that contribute to DS pathophysiology. This study aims to comprehensively investigate the intricate
nuclear-metabolic interplay in DS. Our multifaceted approach utilizing human stem cell and mouse models will
decode the molecular, cellular, and tissue level role of cellular metabolism on the brain etiologies observed in
DS. We aim to characterize and modulate the nuclear-metabolic axis at three levels during neurodevelopment:
1) glycolysis, 2) lipid/cholesterol metabolism, and 3) histone acetylation. Findings from this study will provide
critical insights into the mechanisms underlying aberrant brain development in DS and will uncover promising
therapeutic strategies to ameliorate the impact of dysfunctional neurogenesis. Further, our work will shed light
on the broader understanding of the nuclear-metabolic interplay during fate specification, differentiation,
proliferation and brain morphogenesis. Ultimately, this research will provide the blueprint for exploring the role
of the nuclear-metabolic axis broadly in neurodevelopmental disorders, beyond DS, and provide unexplored
therapeutic avenues to improve the lives of individuals living with this disorder.

## Key facts

- **NIH application ID:** 10945992
- **Project number:** 1R01HD115635-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Hiruy Sibhatu Meharena
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $676,644
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945992

## Citation

> US National Institutes of Health, RePORTER application 10945992, Nuclear-Metabolic Interplay in Down syndrome (1R01HD115635-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10945992. Licensed CC0.

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