# Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

This Administrative Supplement is in response to NOT-AG-20-034, entitled ‘Alzheimer’s-focused administrative
supplements for NIH grants that are not focused on Alzheimer’s disease’. The overall goal of this supplement
is to use our existing award, focused on how diabetes-dependent disruption of the circadian clock contributes
to the adverse effects of diabetes on the heart, as the platform to assess the impact of these factors on
Alzheimer’s disease (AD) and its related dementias (ADRD). The parent application tests the hypothesis that
changes in the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) during diabetes impairs
circadian regulation of autophagy/mitophagy in cardiac dysfunction. Interestingly, circadian dysregulation,
diabetes, perturbation of protein O-GlcNAcylation, mitochondrial dysfunction and autophagy/mitophagy have
also all been linked to AD. It is currently unknown whether 1) O-GlcNAcylation, mitophagy, and mitochondrial
function in the brain are circadian regulated and affected by diabetes; and 2) whether circadian, O-GlcNAc and
mitophagy manipulations change cognition and neuropathology. Thus our current supplement application will
test the hypothesis that AD and ADRD related neurological and pathological phenotypes are a
consequence of dysregulation of the circadian clock-O-GlcNAcylation axis resulting in impaired
neuronal mitophagy and bioenergetics that is exacerbated by T2DM. The same mouse genetic and
pharmacological manipulations, parallel histology and biochemical methods will be used in the brain
in the supplement project, as described in the parent project. We will perform studies with the
following 2 aims: 1) Determine whether the circadian regulation of O-GlcNAcylation, mitophagy and
mitochondrial function in the brain, as well as cognition and neuropathology, are affected by diabetes; and 2)
Determine whether genetic perturbation of mitophagy, pharmacological enhancement of mitophagy, and
pharmacological perturbation of circadian clock affect O-GlcNAcylation, mitophagy, mitochondrial function,
cognition and neuropathology. The goal is to gain new fundamental insights into aspects of circadian disruption
and diabetes in the pathogenesis of AD, which have not been investigated previously. New insights gained
from this study will help identify innovative approaches for alleviating cognitive and neuropathological deficits in
AD.

## Key facts

- **NIH application ID:** 10288158
- **Project number:** 3R01HL142216-04S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JOHN C CHATHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 3
- **Project period:** 2018-04-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288158

## Citation

> US National Institutes of Health, RePORTER application 10288158, Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes (3R01HL142216-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288158. Licensed CC0.

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