权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

反应性星形胶质细胞在局灶性缺血性中风后神经再生和大脑恢复中的作用

基本信息

批准号：
10458598
负责人：
Shinghua Ding
金额：
$ 35.11万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458598
关键词：
Action Potentials Acute Adult Affect Affinity Chromatography Apoptotic Astrocytes Attenuated Behavioral Biological Assay Brain Brain Infarction Brain Injuries Cell Line Cell Proliferation Cessation of life DLG4 gene Dendrites Dependovirus Electrophysiology (science)Exhibits Gene Expression Glutamates Goals Hindlimb Histologic Human Image Infarction Injections Ischemia Ischemic Stroke Knockout Mice Lead Measurement Mediating Methods Microscopy Molecular Molecular Genetics Morphology Motor Cortex Mus Natural regeneration Nerve Regeneration Neuroglia Neurons Play Process Proteins Quantitative Reverse Transcriptase PCR Recombinants Recovery Recovery of Function Ribosomes Role Signal Transduction Synapses Synaptic plasticity Synaptophysin Technology Testing Therapeutic Time Tissues Transcript Translating Vertebral column Viral Virus Western Blotting adeno-associated viral vector adult neurogenesis base behavior test behavioral outcome brain repair conditional knockout disability functional outcomes gain of function genetic approach glial cell-line derived neurotrophic factor immunocytochemistry improved in vivo insight loss of function motor behavior mouse model neuron loss neurotrophic factor neurotropic novel overexpression patch clamp promoter stroke outcome stroke therapy synaptic function synaptogenesis tool treatment strategy two-photon

项目摘要

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 molecular, cellular and functional insights into the brain recovery processes after FIS in the context of glia-neuron interactions, reveal potential strategies for stroke therapy, and thus has both scientific and translational significances.

项目总结

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glial cell line derived neurotrophic factor in brain repair after focal ischemic stroke.

DOI：
10.4103/1673-5374.332141
发表时间：
2022-08
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Zhang Z;Zhang N;Ding S
通讯作者：
Ding S

Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice.

DOI：
10.1186/1471-2202-15-58
发表时间：
2014-05-02
期刊：
BMC neuroscience
影响因子：
2.4
作者：
Li H;Zhang N;Lin HY;Yu Y;Cai QY;Ma L;Ding S
通讯作者：
Ding S

Pre-B-cell colony-enhancing factor protects against apoptotic neuronal death and mitochondrial damage in ischemia.

前 B 细胞集落增强因子可防止缺血时神经元凋亡和线粒体损伤。

DOI：
10.1038/srep32416
发表时间：
2016-08-31
期刊：
Scientific reports
影响因子：
4.6
作者：
Wang X;Li H;Ding S
通讯作者：
Ding S

Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death.

DOI：
10.1016/j.celrep.2017.08.022
发表时间：
2017-08-29
期刊：
Cell reports
影响因子：
8.8
作者：
Wang X;Zhang Q;Bao R;Zhang N;Wang Y;Polo-Parada L;Tarim A;Alemifar A;Han X;Wilkins HM;Swerdlow RH;Wang X;Ding S
通讯作者：
Ding S

Acid-Sensing Ion Channels in Glial Cells.