# Evaluating novel transcription factors in regulating astrocyte identity, reactivity, and their roles in neurodegenerative disease pathogenesis

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2024 · $427,625

## Abstract

Abstract
This proposal leverages a new interdisciplinary collaboration between Drs. Guoyan Zhao and Erik Musiek to
define the transcriptional control of astrocyte identities, reactivities, and their roles in in Alzheimer disease (AD)
and Parkinson disease (PD) pathogenesis. AD and PD are heterogeneous, multifactorial disease that selectively
affects certain regions of the brain. Astrocytes are a major glial cell type in the central nervous system that play
critical roles in neural circuit function and brain homeostasis. Accumulating evidence supports astrocyte as a
major contributor of the neurodegenerative processes in AD and AD Related Dementias (AD/ADRD). In our
recently published work, we identified three evolutionarily conserved astrocyte subpopulations which had unique
marker gene expressions shared by the corresponding populations across multiple brain regions and different
disease conditions. However, astrocytes do exhibit regional differences and transcriptomic changes in disease
conditions linked to amyloid pathology, tauopathy, neuronal death, and neurodegenerative diseases, suggesting
that astrocytes may contribute to regional differences in disease susceptibility. From this work, we have identified
ten candidate TFs that exhibited regional differential expression patterns in human astrocytes whose expressions
were dysregulated in disease conditions. Furthermore, these TFs are either known AD risk genes or have known
functions in regulating cell activation or inflammatory response in cell types other than astrocyte. In this proposal,
we will use our established in vitro and in vivo mouse experimental systems and the cutting-edge technologies
of spatial transcriptomics and scRNA-seq to systematically evaluate each candidate TF in regulating astrocyte
property and AD/PD pathogenesis. In Aim 1, we will perform in vitro experimental investigation of candidate TFs
in regulating astrocyte property and neurodegenerative disease pathogenesis.
We will
manipulate candidate TF
expression in primary murine astrocyte-enriched cultures
properties of astrocyte with and without TF manipulation,
astrocyte cultures to sustain growth of mouse cortical
and human astrocytes cell line assess the
including morphological changes, the ability of
neurons, cytokine/chemokine expression,
and
and
phagocytosis capability. In
Aim 2 we will perform MERSCOPE spatial transcriptomic analysis to assess region-
specific expression of candidate TFs. In Aim 3 we will perform in vivo gene knock-down and overexpression
analyses to assess the function of candidate TFs in regulating astrocyte reactivity, neurodegenerative disease
pathology, and the impact on other cell types. If funded and successfully implemented this proposal will provide
validated TFs that regulate astrocyte activation and/or AD/PD pathology relevant to human disease pathogenesis.
These TFs are excellent candidate targets for the development of effective AD or PD treatment strategies.

## Key facts

- **NIH application ID:** 10985311
- **Project number:** 1R21AG089851-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Erik Steven Musiek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,625
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985311

## Citation

> US National Institutes of Health, RePORTER application 10985311, Evaluating novel transcription factors in regulating astrocyte identity, reactivity, and their roles in neurodegenerative disease pathogenesis (1R21AG089851-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985311. Licensed CC0.

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