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Regulation of Astrocyte Heterogeneity and Developmental Maturation in the CNS

中枢神经系统星形胶质细胞异质性和发育成熟的调节

基本信息

批准号：
9199226
负责人：
F Rob JACKSON
金额：
$ 56.13万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-20 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199226
关键词：
Adenoviruses Affinity Chromatography Alleles Astrocytes Biological Models Cell Maturation Communities Corpus striatum structure Coupled Data Development Disease Progression Drosophila genus Enterobacteria phage P1 Cre recombinase Excitatory Amino Acid Transporter 2 Exhibits Fluorescence-Activated Cell Sorting Foundations Functional disorder Future Gene Activation Gene Deletion Genes Genetic Genetic Models Genetic Screening Glutamate Transporter Heterogeneity Hippocampus (Brain)Homologous Gene Human Hypothalamic structure Knowledge LoxP-flanked allele Measures Mental disorders Methods Molecular Molecular Genetics Molecular Profiling Morphology Mouse Strains Mus Neuraxis Neuroglia Neurons Neurosciences Research Nucleus Accumbens Pathogenesis Pattern Physical shape Physiology Population Population Heterogeneity Procedures Process RNA Interference Regulation Reporter Research Ribosomes Rosa Synapses Synaptic Transmission System Techniques Technology Thalamic structure Transgenic Mice Translating base cell type differential expression fly genetic analysis genetic approach in vivo insight knock-down loss of function mouse Cre recombinase mutant nervous system disorder neurotransmission novel novel marker promoter public health relevance putamen tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Astrocytes are now recognized as active components of mature synapses; they structurally ensheath synapses and modulate neurotransmission in the central nervous system (CNS). Astrocyte dysfunction has been implicated in various neurological disorders and has been shown to actively modulate disease progression. Although astrocytes undergo a developmental maturation process in which subtypes form unique and elaborate morphologies and express overlapping but distinct molecular signatures, it is unknown how astrocyte heterogeneity arises during development of the CNS and how astrocyte development is regulated, in part because of a lack of appropriate tools for such studies. We propose to use integrated molecular and genetic approaches in Drosophila and mouse to define factors that distinguish astrocyte subtypes and regulate their developmental maturation. In particular, this project will focus on these aims: 1) Molecularly define astrocyte subtypes within the cortex and in different CNS regions using FACS and TRAP approaches; 2) Perform dEAAT1-based genetic screens to identify regulators of astrocyte development; 3) Develop new cre recombinase mice for studying astrocyte heterogeneity and function in vivo. We have generated a large amount of preliminary data demonstrating feasibility for the three aims summarized above. By characterizing molecular signatures of astrocyte subtypes in the CNS and identifying regulators of astrocyte development, this project will provide markers for astrocyte subtypes in the cortex and novel insights about how astrocyte maturation occurs. The development of a new cre recombinase driver mouse line will facilitate the selective deletion/activation of genes in astrocytes of the cortex, a region for which an existing astrocyte cre driver line is not very effective. Knowledge of astrocyte heterogeneity and new tools for studying it are critical for understanding how astrocytes become dysfunctional and how distinct classes of astrocytes contribute to the pathogenesis of psychiatric disorders.

描述（由申请人提供）：星形胶质细胞现在被认为是成熟突触的活性成分；它们在结构上包裹着突触并调节中枢神经系统（CNS）的神经传递。星形胶质细胞功能障碍与各种神经系统疾病有关，并已被证明可以积极调节疾病进展。尽管星形胶质细胞经历一个发育成熟过程，其中亚型形成独特而复杂的形态，并表达重叠但不同的分子特征，但尚不清楚中枢神经系统发育过程中星形胶质细胞异质性如何产生以及星形胶质细胞发育如何调节，部分原因是缺乏适合此类研究的工具。我们建议在果蝇和小鼠中使用综合分子和遗传学方法来定义区分星形胶质细胞亚型并调节其发育成熟的因素。特别是，该项目将重点关注以下目标：1）使用 FACS 和 TRAP 方法从分子角度定义皮质内和不同 CNS 区域的星形胶质细胞亚型； 2) 进行基于 dEAAT1 的遗传筛选，以确定星形胶质细胞发育的调节因子； 3) 开发新的cre重组酶小鼠用于研究星形胶质细胞异质性和体内功能。我们已经生成了大量初步数据，证明了上述三个目标的可行性。通过表征中枢神经系统中星形胶质细胞亚型的分子特征并识别星形胶质细胞发育的调节因子，该项目将为皮质中星形胶质细胞亚型提供标记，并提供关于星形胶质细胞成熟如何发生的新见解。新的cre重组酶驱动小鼠系的开发将促进皮质星形胶质细胞中基因的选择性删除/激活，而现有的星形胶质细胞cre驱动系对于该区域不是很有效。了解星形胶质细胞异质性和研究它的新工具对于理解星形胶质细胞如何变得功能障碍以及不同类别的星形胶质细胞如何促进精神疾病的发病机制至关重要。