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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：
10213839
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213839
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 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