# Developing astrocyte, neuron, and microglial 3D organoids to model key aspects of human pathology

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $11,147

## Abstract

Project Summary
Astrocytes are the most abundant non-neuronal cell types in the brain. Astrocytes promote neuronal survival,
provide neurons with metabolic substrates, help recycle synaptic neurotransmitters, regulate blood flow, buffer
extracellular ions, induce or eliminate synapses and regulate synaptic transmission and synaptic plasticity.
Most recently, it has been shown that when specific signaling pathways are compromised, astrocytes can
become reactive and can start eliminating synapses ultimately; leading to neuronal cell death during both
natural aging and age-related neurodegenerative diseases. Our research aims to understand how astroglial
activation is initiated in Alzheimer’s Disease (AD). We will focus on this question by studying a gene called
granulin (GRN). This gene has been linked to aging in the human cortex and loss of GRN inevitably leads to
astroglial activation and a devastating neurodegenerative disease termed Frontal Temporal Lobar
Degeneration (FTLD). To begin to tackle this question, we propose investigating the molecular mechanisms of
GRN signaling on astroglial activation. The goal of our work is to understand how normal GRN function
prevents protein mislocalization in healthy aging human neurons, and how loss of GRN causes these same
proteins to mislocalize in neurons: leading to neuronal death in AD and FTLD. Based on recent findings that
rodent astrocytes and human astrocytes are genetically and morphologically very different, we will use human
cells to study this question and set up a novel 3D human induced pluripotent stem cell (iPSC) organoid system
to incorporate human neurons, astrocytes and microglia. We will then analyze the mislocalization of specific
protein in GRN positive and GRN knockout organoids. We will also study the signaling differences between
GRN positive and GRN knockout astrocytes, and focus on the innate immune complement pathway and how
GRN affects this pathway. Collectively, these studies will allow us to identify the factors in astrocytes that
promote brain homeostasis, aging and disease.

## Key facts

- **NIH application ID:** 10224554
- **Project number:** 3R03AG063157-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Erik M Ullian
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $11,147
- **Award type:** 3
- **Project period:** 2019-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224554

## Citation

> US National Institutes of Health, RePORTER application 10224554, Developing astrocyte, neuron, and microglial 3D organoids to model key aspects of human pathology (3R03AG063157-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10224554. Licensed CC0.

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