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Astrocytes are a primary target of neuronal-derived BDNF: a novel mechanism for dysfunction in Rett Syndrome

星形胶质细胞是神经源性 BDNF 的主要靶标：雷特综合征功能障碍的新机制

基本信息

批准号：
9256598
负责人：
Leanne Holt
金额：
$ 4.4万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256598
关键词：
Address Adult Affect Animals Astrocytes Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Breathing Cell physiology Cells Complex Coupled Data Development Disease Exhibits Female Foundations Functional disorder Gap Junctions Gastrointestinal Diseases Genetic Techniques Genetic Transcription Goals Golgi Apparatus Grant Growth Factor Hand Hippocampus (Brain)Homeostasis Human Imaging Techniques In Vitro Knock-out Label Lead Light Maintenance Mediating Mediator of activation protein Messenger RNA Methyl-CpG-Binding Protein 2 Molecular Genetics Morphology Mutation Neuraxis Neurodevelopmental Disorder Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Patients Pharmacology Population Process Publications Publishing RNA Sequences Receptor Signaling Rett Syndrome Rodent Role Seizures Signal Transduction Spinal Cord Structure Synapses Testing Time Up-Regulation Work cell growth cell type critical period experience in vivo mRNA Expression mature animal nervous system disorder neurodevelopment neuronal cell body neuronal growth neurotransmitter reuptake novel postnatal receptor reduce symptoms response stereotypy

项目摘要

Project Summary/Abstract Mature astrocytes are arguably the most morphologically complex cells in the central nervous system. This complexity is associated with several of the most well characterized functions of this cell type, including neurotransmitter reuptake, K+ homeostasis, and blood-brain barrier maintenance. While we know the developmental time window when astrocyte morphological maturation and refinement occurs, we know little else about this process. Brain derived neurotrophic factor (BDNF) is a critical growth factor secreted largely by neurons and involved in the development and maturation of neurons, including neuronal growth and synapse refinement. Preliminary data we have generated for this grant demonstrates that astrocytes express high levels of the BDNF receptor TrkB when compared to neurons. In particular, the truncated version of TrkB, TrkB.T1 is the predominate receptor expressed. TrkB.T1 expression is highest in astrocytes during the critical period of astrocyte morphological refinement and maturation, a developmental time window which also happens to coincide with highest neuronal BDNF expression levels. Loss of BDNF expression is a hallmark of neurodevelopment disorder Rett Syndrome, and recent publications indicate that astrocytes have a significantly reduced morphological complexity and are dysfunctional in this disease. These findings have led us to the hypothesis that BDNF/TrkB.T1 signaling is an important mediator of astrocyte morphological maturation and that reduced neuronal BDNF expression contributes to astrocyte dysfunction by modulating astrocyte morphology in Rett Syndrome. We propose to examine BDNF’s influence on astrocyte morphology utilizing a combination of in vitro and in vivo molecular, genetic, and imaging techniques. Additionally, we will examine if reduced BDNF/TrkB.T1 signaling contribute to aberrant astrocyte morphology in Rett syndrome which may shed light on how astrocyte dysfunction contributes to the pathophysiology of this devastating disease.

项目总结/文摘