# Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $351,064

## Abstract

Project Summary
The adult brain has a remarkable capacity to recover from focal ischemic stroke (FIS). Astrocytes are the most
numerous and diverse glial cells in CNS and intimately interact with neurons to support and regulate their
functions. After FIS, astrocytes in the PIR exhibit dynamic changes in morphology, proliferation and gene
expression especially in the peri-infarct region (PIR). These astrocytes are called reactive astrocytes (RAs).
However, whether and how reactive astrocytes (RAs) affect brain recovery after FIS in the context of
astrocyte—neuron interactions largely remain unexplored. In our preliminary study, we found GDNF, a potent
neurotrophic factor, is dramatically upregulated in the ischemic hemisphere and RAs after photothrombosis
(PT)-induced FIS. Furthermore, we found that deletion of astrocytic GDNF reduces adult neurogenesis in
normal brain, and increases brain infarction and attenuates cell proliferation in the PIR after PT. Based on
these strong preliminary results, we hypothesize that RAs-derived GDNF plays an important role in neural
regeneration and functional brain recovery after FIS. The prohect goal is to determine whether and how RAs-
derived GDNF stimulates synaptic regeneration and remodeling of surviving neurons in the PIR and improves
long-term stroke outcomes after FIS. To achieve this goal, we have developed interdisciplinary technologies
including self-complementary adeno-associated virus (scAAV) vectors and Glast-CreERT2:GDNFf/f mice to
specifically overexpress or delete GDNF in RAs during post FIS time, in vivo two photon (2-P) long-term
microscopy, electrophysiology, immunocytochemistry, Western blot (WB) analysis, brain damage and neuronal
death assays and behavioral tests. We propose three specific aims. In Aim 1, we will test the hypothesis that
RAs-derived GDNF can enhance synaptogenesis to stimulate neural regeneration in the PIR after FIS. We will
determine the effects of RAs-derived GDNF on the expression of neuronal proteins involving synaptic function
and plasticity in the PIR; using TRAP (translating ribosome affinity purification) method we will further identify
neuronal transcript changes at translational status in the PIR. In Aim 2, we will test the hypothesis that RAs-
derived GDNF can promote structural and functional synaptic remodeling of surviving neurons in the PIR after
FIS. Using in vivo long-term 2-P imaging we will determine the effect of RAs-derived GDNF on spine turnover
(i.e., spine formation and elimination), glutamate release and Ca2+ signaling in the same dendrites of surviving
neurons in the PIR. We will conduct patch-clamp recording on surviving neurons in the PIR to determine the
effect of RAs-derived GDNF on functional synaptic plasticity. In Aim 3, we will test the hypothesis that
astrocytic GDNF can improve long-term stroke outcomes. We will evaluate the effect of RAs-derived GDNF on
long-term histological and behavioral outcomes. Our project will provide novel mole...

## Key facts

- **NIH application ID:** 9976583
- **Project number:** 5R01NS069726-08
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Shinghua Ding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,064
- **Award type:** 5
- **Project period:** 2010-05-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976583

## Citation

> US National Institutes of Health, RePORTER application 9976583, Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke (5R01NS069726-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976583. Licensed CC0.

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