# Molecular mechanisms of mammalian circadian clock function

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $265,981

## Abstract

Abstract
 Alzheimer’s disease (AD) is the most common neurodegenerative disease among the
elderly and is characterized by a global decline in cognition including memory loss and reduced
reasoning power, followed by severe neurodegeneration and death. In addition to the cognitive
problems, a common manifestation of AD is a major disruption in sleep-wake cycles, with
patients exhibiting excessive daytime sleepiness or changes in sleep timing and reduced
circadian amplitudes. Familial AD cases only account for ~1% of afflicted individual, while the
rest result from sporadic mutations that are likely influenced by many environmental and genetic
factors. In these sporadic cases, the cause of the neuronal cell death is not known but appears
to be through various cellular insults that result in toxic aggregations of amyloid-β (Aβ) protein
(amyloid plaques) and hyperphosphorylated tau (neurofibrillary tangles; NFT) and increased
oxidative stress. Although the existing data make difficult to determine whether oxidative stress
or protein aggregation is the initiating event, these two processes clearly impact each other, and
a growing body of evidence implicates oxidative stress as being involved in at least the
propagation of cellular injury that leads to neuropathology in AD. In this supplemental
application, we will explore the role of the circadian protein Nocturnin in the pathogenesis of AD.
Our data suggest that Nocturnin is an important modulator of oxidative stress, with higher levels
exacerbating stress and lower levels providing protective effects. Genome-Wide Association
Studies (GWAS) has identified a variant in Nocturnin as one of the rare protective variants for
AD, suggesting that plays a role in excessive oxidative stress responses that contribute to
pathogenesis and we will examine this link through mechanistic work in both cells and mice in
this proposal. There are currently no treatments that prevent neuronal cell loss in AD and we
hypothesize that reduction of oxidative stress through the inhibition of Nocturnin might break
the cycle of cell death.

## Key facts

- **NIH application ID:** 10121651
- **Project number:** 3R35GM127122-03S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla B. Green
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,981
- **Award type:** 3
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121651

## Citation

> US National Institutes of Health, RePORTER application 10121651, Molecular mechanisms of mammalian circadian clock function (3R35GM127122-03S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10121651. Licensed CC0.

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