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Grants > Determining How Circadian Rhythm Regulates Sleep Fragmentations in Tauopathy Updated On: Feb. 2, 2025
Alzheimer's Disease Research Grant

Determining How Circadian Rhythm Regulates Sleep Fragmentations in Tauopathy

Tau
a headshot of Dr. Tabuchi

Principal Investigator

Masashi Tabuchi, PhD

Case Western Reserve University School of Medicine

Cleveland, OH, USA

About the Research Project

Program

Alzheimer's Disease Research

Award Type

Standard

Award Amount

$300,000

Active Dates

July 01, 2021 - June 30, 2025

Grant ID

A2021043S

Goals

The goal of this project is to elucidate how sodium channel dynamical states modulate tau pathology in circadian neurons to alter circadian rhythms and sleep.

Summary

In Aim 1, we will evaluate how inactivation states of voltage-gated sodium channels alter tau proteostasis, core clock system regulation, and circadian activity. In Aim 2, we will investigate the effect of pharmacological manipulations of inactivation states of voltage-gated sodium channels on clock neuron electrophysiology, sleep behavior, cognition, and lifespan in the adult Drosophila brain. In Aim 3, we will demonstrate that the inactivation states of voltage-gated sodium channels are altered in the iPS cells derived from human patients.

Unique and Innovative

By using Drosophila, the research proposal can precisely but rapidly capture behaviorally important molecular phenotypes of Alzheimer’s disease, and we can validate the conservation of these phenotypes in human iPS cell-derived neurons, by using our state-of-the-art data acquisition methodology of simultaneous electrophysiology and arousal/sleep measurements with sophisticated machine learning platforms to construct mathematical models to extract the features of the temporal structure of neural activity patterns. We believe that this approach is novel, and will attract worldwide attention.

Foreseeable Benefits

Completion of our study will help us address the gap in our knowledge of how alterations in voltage-gated channel states contribute to Alzheimer’s disease and related tauopathies, in the context of circadian regulation of sleep. Further, it will help pave the way towards the development of new therapeutic strategies for Alzheimer’s disease.