# Function of reactive astrocytes in aging and neurodegenerative disease

> **NIH NIH K00** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $85,884

## Abstract

ABSTRACT/PROJECT SUMMARY
Reactive astrocytes (RAs) are a feature of normal aging and neurodegeneration. RAs drastically change their
morphology and gene expression, notably increasing the expression of glial fibrillary acidic protein (GFAP) in
response to injury or inflammation. GFAP is the major intermediate filament protein of mature astrocytes.
Autosomal dominant mutations in GFAP cause the rare and fatal leukodystrophy, Alexander Disease (AxD). In
AxD patients, astrocytes accumulate pathological GFAP aggregates (Rosenthal fibers; RFs) and become
reactive. However, the mechanisms linking >70 different GFAP mutations to RF formation and other disease-
relevant phenotypes in AxD remain unknown. My extensive preliminary data show that aberrant
phosphorylation promotes GFAP aggregation, and that this modification is a marker of AxD severity,
independently of the disease mutation. Further, I show that site-specific GFAP phosphorylation is associated
with increased proteolysis by caspase-6, but whether the two are directly linked is unknown. I hypothesize
that coordinated cross-talk between casein kinase (CK2) and caspase-6 promotes defective GFAP
proteostasis to exacerbate the reactive phenotype of AxD astrocytes. For the F99 phase, I propose to use
pharmacological and genetic strategies to inhibit CK2 and caspase-6 activity in order to characterize their roles
in vitro using the astrocyte model that I developed (Aim 1.1), and in vivo utilizing an AxD mouse model (Aim
1.2). I will master iPSC gene editing with CRISPR/Cas9 to generate CK2 and caspase-6 knockouts and iPSC
handling and differentiation to astrocyte and neurons (Aim 1.1), and I will apply these techniques to my
postdoctoral project (Aim 2). For the K00 phase, I will investigate the functions of RAs in Alzheimer's disease in
the lab of Dr. Mel Feany. Proteoglycans (PGs) are among the most highly upregulated genes in aging and
RAs. Preliminary data from Dr. Feany's lab identified genetic interactions between PGs and models of
neurodegeneration in the fly. I hypothesize that RAs produce an imbalance of PGs in the extracellular matrix,
which creates an environment that is inhibitory to neuronal growth and remodeling. To model the mechanical
changes known to occur in AD brain, I will develop a novel model to study RAs by culturing iPSC-astrocytes on
substrates of different stiffness. Additionally, I will generate knockouts of candidate PGs in iPSCs and
differentiate them to reactive and non-reactive astrocytes. I will use in vivo fly models and co-cultures of iPSC-
astrocytes and neurons to examine the role of PGs in toxicity of RAs. My thesis project and my future
postdoctoral studies will provide a rich training experience that will prepare me for a career as an independent
investigator leading a rigorous research program at the nexus of aging and glial biology.

## Key facts

- **NIH application ID:** 10480931
- **Project number:** 5K00AG068523-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Rachel Battaglia
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $85,884
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480931

## Citation

> US National Institutes of Health, RePORTER application 10480931, Function of reactive astrocytes in aging and neurodegenerative disease (5K00AG068523-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480931. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*