Grant Abstract: Impact of Time-Restricted Feeding in Reducing Cancer Risk Through Optimizing Mitochondria Function

Grant Number: 5R01CA258221-03
PI Name: Panda
Project Title: Impact of Time-Restricted Feeding in Reducing Cancer Risk Through Optimizing Mitochondria Function

Abstract: This request for an administrative supplement is submitted in response to NOT-AG-22-025, Alzheimer' s-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease. Disruption of circadian rhythm and sleep, long considered to be associated with Alzheimer's Disease and related dementia (ADRD), is increasingly recognized as an early contributor to disease onset and progression. Optimum circadian rhythm is known to sustain mitochondria function and consequently homeostatic function of the brain. At the molecular level, circadian clock components and their immediate downstream targets are linked to transcriptional regulation of genes implicated in the homeostatic regulation of many cellular processes and organelles including that of mitochondria in neurons, astrocytes, and glia. Circadian clock disruption is known to increase brain inflammation, dysfunction of mitochondria and increased production of reactive oxygen species, all of which may increase the risk for ADRD. Conversely, behavioral or pharmacological approaches to boost circadian rhythm or function of clock components are known to improve mitochondria function. Time-restricted feeding is a novel dietary intervention which involves consuming all caloric intake within a consistent window of 8-10 hours in the active phase of the animals without explicit attempt to reduce calorie intake. This approach is known to improve the amplitude of circadian clock, mitochondria volumes, mitochondria function and significant reduction of markers of mitochondria stress in peripheral metabolic organs. Animal models of neurodegeneration also show improved sleep and motor control under TRF. So far, most of the TRF studies are done in wild type mice and only a few short-term studies have shown mouse models of AD can adapt to TRF, thus demonstrating feasibility. However, there are major knowledge gaps- the molecular mode of action of TRF on mitochondria gene expression and function in brain regions relevant to ADRD. This supplemental fund requested will be used to subject well-validated mouse model of AD to TRF and systematic and comprehensive measurement of transcriptome changes in the hippocampus and amygdala of this mouse model. These critical results obtained with the supplemental budget will form the foundation for future mechanistic and translational research to use TRF as an approach to reduce the risk of AD and/or to reduce the progression of disease. PUBLIC HEALTH RELEVANCE: . Dysfunction of mitochondria is a risk factor for Alzheimer’s Disease and related dementia (ADRD). Therefore, interventions that improve mitochondria function can be a new strategy to prevent or treat Alzheimer's disease (AD). This proposal will test the effectiveness of time-restricted feeding that is known to improve mitochondria function as a dietary intervention strategy to reduce AD risk in a laboratory model.

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