# Redesigning a Neuron's Breath: A Modern Twist to Classical Oxygen Biology

> **NIH NIH DP5** · J. DAVID GLADSTONE INSTITUTES · 2020 · $452,923

## Abstract

PROJECT SUMMARY/ABSTRACT
 Oxygen is one of the most used substrates in the human body. When oxygen deprivation exceeds the
buffering capacity of the human body, there are devastating effects on health and survival. For example, three
of the five leading causes of death in the US are a consequence of impaired oxygenation – heart disease,
respiratory disease and stroke. Indeed, over 400,000 individuals suffer from a stroke each year in the US alone,
leaving a great unmet need for new therapies. By uncovering how tissues sense and adapt to variations in
oxygen tensions, we can better understand and treat such conditions of impaired oxygenation.
 The mitochondrial electron transport chain (ETC) consumes 90% of the body's oxygen, while providing
90% of the ATP supply. Interestingly, the reliance on the ETC for energy production varies substantially across
tissues. The remaining oxygen consumption arises from several hundred oxygen-dependent reactions that also
occur in a highly tissue-specific manner. Moreover, hypoxia tolerance varies drastically across different tissues.
At one extreme, the brain can only survive for several minutes without oxygen. At the other extreme, skeletal
muscle can survive several hours of anoxia without permanent damage. This wide range of metabolic flexibilities
across the human body serves as a fascinating and useful tool to study adaptive mechanisms for hypoxia.
 Traditionally, comparative physiologists have drawn inspiration from extreme organisms (e.g. painted
turtles, Weddell seals) that can survive without oxygen for hours or days at a time. However, these strategies
are rarely translatable as humans do not possess the unique metabolic pathways or physiology of these
organisms. Instead, I propose a modern twist to a classical problem – the use of comparative metabolism across
the most extreme tissues to identify oxygen sensing and adaptive pathways. More specifically, I propose varying
oxygen tensions and (Aim 1) comparing the bioenergetics and metabolism between primary neurons vs. skeletal
myotubes, (Aim 2) defining their respective genetic and nutrient dependencies and (Aim 3) using these insights
to manipulate adaptive pathways for cerebral hypoxia in a mouse model of stroke. We hypothesize that unique
metabolic pathways underlie the differences in ischemia sensitivity of neurons vs. skeletal myotubes. By
understanding such differences, we hope to uncover novel hypoxia adaptations and apply them to disorders of
impaired oxygenation such as ischemic stroke.

## Key facts

- **NIH application ID:** 10447352
- **Project number:** 7DP5OD026398-04
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Isha Himani Jain
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $452,923
- **Award type:** 7
- **Project period:** 2021-07-08 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447352

## Citation

> US National Institutes of Health, RePORTER application 10447352, Redesigning a Neuron's Breath: A Modern Twist to Classical Oxygen Biology (7DP5OD026398-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10447352. Licensed CC0.

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