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Transcriptional Control of Gliogenesis in the CNS

中枢神经系统胶质生成的转录控制

基本信息

批准号：
10447125
负责人：
Benjamin Deneen
金额：
$ 40.01万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2010-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447125
关键词：
Address Adult Anatomy Area Astrocytes Behavior Biological Assay Biology Blood - brain barrier anatomy Brain Brain region Buffers Calcium ChIP-seq Coupled Data Development Disease Exhibits Genes Genetic Transcription Glioma Goals Health Hippocampus (Brain)Impairment Knowledge Laboratories Learning Link Long-Term Potentiation Malignant Neoplasms Membrane Memory Metabolic Molecular Morphology Mus NFIA gene Nature Neuroglia Neurons Neurosciences Neurotransmitters Physiological Physiological Processes Physiology Play Population Process Property Regulation Reporter Role Schizophrenia Series Synapses Transcriptional Regulation Transgenic Mice autism spectrum disorder base gene network gliogenesis interest nervous system disorder neuronal circuitry novel response synaptogenesis transcription factor transcriptome transcriptome sequencing white matter injury

项目摘要

Our studies on astrocyte diversity in the adult brain, revealed that NFIA is highly expressed in adult astrocytes, across several brain regions. This led us to hypothesize that, in addition to its pivotal role in astrocyte development, NFIA may also contribute to astrocyte function in the adult. This hypothesis addresses a key “gap area” in our knowledge of astrocyte biology as the transcriptional mechanisms that regulate adult astrocyte function are unknown.To ascertain whether NFIA contributes to mature astrocyte function, we generated new transgenic mouse lines that specifically eliminates it in adult astrocytes. Preliminary studies with these mice revealed that astrocytes lacking NFIA exhibit region-specific changes in morphology, that are coupled with impaired Ca2+ activity. These changes in astrocyte function directly impact neuronal physiology, as synaptic activity is impaired and the induction of long term potentiation (LTP) is inhibited. Accordingly, this inhibition of LTP corresponds with deficits in learning and memory behaviors. Together, these observations reveal a novel transcriptional mechanism regulating adult astrocyte function and associated neuronal circuits, while also defining a new role for NFIA in the brain. Therefore, based on the strength of these preliminary data, we propose the following specific aims. In specific aim 1, we will determine how loss of NFIA influences astrocyte morphology and function across a diverse range of brain regions, over a series of timepoints, post-deletion of NFIA. Functional studies will include assessing astrocyte membrane conductance and calcium responses using genetically encoded GCaMP reporters. In specific aim 2, we will focus on the hippocampus and determine how loss of NFIA in astrocytes influences neuronal physiology, circuit function, and associated behaviors. These studies will make use of basic physiological studies to assess basal and evoked/plasticity responses in neurons. In specific aim 3, we have identified a set of candidate NFIA target genes that we will functionally validate and in the second part of this aim will identify NFIA target gene networks in astrocytes, across diverse brain regions to decode region specific vulnerabilities to NFIA loss in the adult brain.

我们对成人大脑星形胶质细胞多样性的研究表明，NFIA在成人大脑中高度表达。成年星形胶质细胞，跨越几个大脑区域。这使我们假设，除了它的在星形胶质细胞发育中起关键作用，NFIA也可能有助于星形胶质细胞功能，成年人了这一假设解决了我们对星形胶质细胞生物学知识中的一个关键“空白区域”，调节成体星形胶质细胞功能的转录机制尚不清楚。无论NFIA是否有助于成熟的星形胶质细胞功能，我们产生了新的转基因小鼠，在成年星形胶质细胞中特异性消除它。对这些小鼠的初步研究显示缺乏NFIA的星形胶质细胞表现出区域特异性的形态学变化，再加上受损的Ca 2+活性。星形胶质细胞功能的这些变化直接影响神经元生理学，因为突触活动受损和长时程增强的诱导 (LTP)被抑制了。因此，LTP的这种抑制对应于学习缺陷，记忆行为总之，这些观察揭示了一种新的转录机制，调节成年星形胶质细胞功能和相关的神经元回路，同时也定义了一种新的 NFIA在大脑中的作用。因此，根据这些初步数据的强度，我们提出以下建议明确的目标。在具体目标1中，我们将确定NFIA的缺失如何影响星形胶质细胞在一系列的时间点上，删除NFIA后。功能研究将包括评估星形胶质细胞膜电导和钙响应使用遗传编码的GCaMP报告。在特定目的2，我们将重点放在海马，并确定如何损失NFIA在星形胶质细胞影响神经元生理、电路功能和相关行为。这些研究将利用基础生理学研究评估基础和诱发/可塑性反应，神经元在具体目标3中，我们已经鉴定了一组候选NFIA靶基因，功能验证，并在第二部分，这一目标将确定NFIA靶基因网络，星形胶质细胞，在不同的大脑区域解码区域特定的脆弱性，以NFIA损失，成人大脑

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental origins of astrocyte heterogeneity: the final frontier of CNS development.

DOI：
10.1159/000343723
发表时间：
2012
期刊：
Developmental neuroscience
影响因子：
2.9
作者：
Chaboub LS;Deneen B
通讯作者：
Deneen B

A glial blueprint for gliomagenesis.

DOI：
10.1038/s41583-018-0014-3
发表时间：
2018-07
期刊：
Nature reviews. Neuroscience
影响因子：
0
作者：
Laug D;Glasgow SM;Deneen B
通讯作者：
Deneen B

Evidence that nuclear factor IA inhibits repair after white matter injury.

DOI：
10.1002/ana.23590
发表时间：
2012-08
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Fancy, Stephen P. J.;Glasgow, Stacey M.;Finley, Meggie;Rowitch, David H.;Deneen, Benjamin
通讯作者：
Deneen, Benjamin

Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds.

响应神经活性化合物的映射星形胶质细胞转录特征。

DOI：
10.3390/ijms22083975
发表时间：
2021-04-12
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Sardar D;Lozzi B;Woo J;Huang TW;Cvetkovic C;Creighton CJ;Krencik R;Deneen B
通讯作者：
Deneen B

Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes.

DOI：
10.1038/nn.3790
发表时间：
2014-10
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
Glasgow, Stacey M.;Zhu, Wenyi;Stolt, C. Claus;Huang, Teng-Wei;Chen, Fuyi;LoTurco, Joseph J.;Neul, Jeffrey L.;Wegner, Michael;Mohila, Carrie;Deneen, Benjamin
通讯作者：
Deneen, Benjamin