# Deciphering the cis-regulatory logic of circadian reprogramming in a mouse model of Alzheimer's Disease

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $34,908

## Abstract

PROJECT SUMMARY
Alzheimer’s Disease (AD), the most common origin of dementia, is frequently accompanied by circadian rhythm
disruption. It is not clear how circadian function relates to neurodegeneration, but deletion of the core circadian
transcription factor (TF) BMAL1 in astrocytes causes both an AD-like cellular phenotype and increased neuron
loss after oxidative stress. Within astrocytes of a mouse model of AD, we have observed a phenomenon known
as circadian reprogramming, in which some genes lose circadian expression while other genes gain circadian
expression. The goal of this proposal is to determine how circadian reprogramming is regulated in astrocytes of
our AD mouse model. I hypothesize that within AD-model astrocytes, BMAL1 interacts with disease-specific TFs
to bind to new genomic locations and cause new genes to become rhythmic. To test this hypothesis, I will 1)
determine whether BMAL1 changes in astrocytes of our AD mouse model to bind to reprogrammed genes (Aim
1), and 2) identify TF motif combinations sufficient to produce circadian gene expression and reprogramming in
astrocytes of our AD mouse model (Aim 2). To characterize BMAL1 binding in Aim 1, I have preliminary data
that FLEXCCs, a technology to record TF binding on a cell type specific level, can be used to record BMAL1
binding. For this project, I will use FLEXCCs to record BMAL1 binding in astrocytes of both wildtype mice and in
our AD mouse model. In Aim 2, I will identify TF motif combinations that drive circadian expression in our AD
mouse model using a Massively Parallel Reporter Assay (MPRA) and capture astrocytic transcripts with
translating ribosome affinity purification and RNA-sequencing (TRAP-seq). This proposal will begin to determine how
the cellular environment of AD-like astrocytes generates circadian reprogramming. By establishing a mechanism
of circadian reprogramming in astrocytes in a mouse model of AD, I will help elucidate how circadian disruption
progresses in AD and uncover new pathways to potentially alter disease course.

## Key facts

- **NIH application ID:** 10831390
- **Project number:** 5F31AG076286-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** India H Reiss
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,908
- **Award type:** 5
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831390

## Citation

> US National Institutes of Health, RePORTER application 10831390, Deciphering the cis-regulatory logic of circadian reprogramming in a mouse model of Alzheimer's Disease (5F31AG076286-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831390. Licensed CC0.

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