Stabilizing Brain Function via Glial Epigenetic Signaling

通过神经胶质表观遗传信号稳定大脑功能

• 批准号: 10656206
• 负责人: Tingting Wang
• 金额: $ 36.97万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656206
• 关键词: Acetyltransferase; Acute; Affect; Alzheimer' s Disease; Animal Behavior; Astrocytes; Biochemical; Bioinformatics; Biological Assay; Brain; Calcium; Calcium Channel; Central Nervous System; Chronic; Chronic Disease; Code; Compensation; Complex; Data; Development; Disease; Drosophila genus; Electrophysiology (science); Epigenetic Process; Epilepsy; Essential Genes; Extracellular Matrix Proteins; Gelatinase A; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Genetic Transcription; Glutamate Receptor; Glutamates; Hippocampus; Histone Acetylation; Homeostasis; Human; Image; Impairment; Individual; Knockout Mice; Ligands; Link; Maintenance; Maps; Mediating; Molecular; Mus; Muscle; Nerve Degeneration; Nervous System; Neuroglia; Neuromuscular Junction; Neurons; Neurotransmitters; Organism; Output; Pathology; Pathway interactions; Physiological; Physiology; Play; Process; Property; RNA Interference; Regulation; Reporter; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Therapeutic; Toxin; Transcriptional Activation; Vesicle; Visualization; Yeasts; autism spectrum disorder; conditional knockout; epigenetic regulation; epigenome; gene discovery; gene function; histone acetyltransferase; insight; neural; neural circuit; neural network; neurodevelopment; neuronal circuitry; neuroregulation; neurotransmission; neurotransmitter release; notch protein; novel; postsynaptic; presynaptic; presynaptic neurons; protein complex; receptor sensitivity; synaptic function; transcriptomic profiling; ubiquitin isopeptidase; virtual

Abstract Homeostatic signaling systems operate as protective mechanisms at the level of individual synapses, neurons, and neural circuits to stabilize brain function and animal behavior. Defective homeostatic regulation causes synapse and neural network instability, which is associated with multiple chronic neural disorders, such as epilepsy, autism and Alzheimer's Disease. Glia are key players that control many different aspects of neural development and synaptic function and are increasingly linked to neurodevelopmental and neurodegenerative pathology. However, virtually nothing is known about whether and how glial signaling is involved in modulating presynaptic neurotransmitter release in synaptic homeostasis. Our preliminary data in Drosophila suggest that impairment of glial signaling completely abolishes presynaptic homeostasis when the nervous system is challenged by acute or long-term synaptic perturbations. We demonstrate that glia respond to chronic inhibition of postsynaptic glutamate receptor sensitivity by modulating their histone acetylation codes. Through a genetic screen in Drosophila, we identified genes that function specifically in glia for the induction and sustained expression of presynaptic homeostasis. Our preliminary data emphasize the importance of epigenetic mechanism-mediated glial signaling in stabilizing synaptic function. We propose to fill the mechanistic gap of understanding the glial signaling in stabilizing the brain function. We will systematically study how the interactions between glia and neuron affect synaptic transmission and synapse stability by using a wide array of genetic, molecular, cellular, electrophysiological, imaging and bioinformatic approaches. We will further extend our studies to mouse hippocampal cultures to examine how astrocyte-expressed epigenetic regulators modulate presynaptic calcium influx, neurotransmitter vesicle pool size and neurotransmitter release. Understanding the function of glial-derived molecules in stabilizing the nervous system confronting chronic harmful stimuli will benefit the development of new treatments and potential therapeutics for neural disorders caused by synapse instability.

摘要 稳态信号系统在单个突触、神经元、 和神经回路来稳定大脑功能和动物行为。体内平衡调节缺陷导致 突触和神经网络不稳定，这与多种慢性神经疾病有关，如 癫痫、自闭症和阿尔茨海默病。神经胶质细胞是控制神经系统许多不同方面的关键角色。 发育和突触功能，并越来越多地与神经发育和神经退行性疾病有关。 病理然而，几乎没有人知道胶质细胞信号是否以及如何参与调节， 突触前神经递质释放的突触内稳态。我们对果蝇的初步研究表明， 神经胶质信号传导的损伤完全破坏了突触前稳态， 受到急性或长期突触扰动的挑战。我们证明神经胶质细胞对慢性抑制 通过调节组蛋白乙酰化密码来调节突触后谷氨酸受体的敏感性。通过基因 在果蝇中进行筛选，我们确定了在神经胶质中特异性发挥诱导和维持作用的基因。 突触前稳态的表达。我们的初步数据强调了表观遗传的重要性 机制介导的神经胶质信号在稳定突触功能。我们建议填补以下机制空白： 了解神经胶质信号在稳定大脑功能中的作用。我们将系统地研究 神经胶质和神经元之间的相互作用影响突触传递和突触稳定性， 分子、细胞、电生理、成像和生物信息学方法。我们将进一步扩大我们的 研究小鼠海马培养物，以检查星形胶质细胞表达的表观遗传调节因子如何调节 突触前钙内流、神经递质囊泡池大小和神经递质释放。了解 神经胶质衍生分子在稳定神经系统对抗慢性有害刺激中的功能将 有利于开发新的治疗方法和潜在的治疗突触引起的神经疾病的药物 不稳定

项目成果

Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses.

• DOI: 10.1111/acel.13989
• 发表时间: 2023-11
• 期刊: Aging cell
• 影响因子: 7.8

Role of α2δ-3 in regulating calcium channel localization at presynaptic active zones during homeostatic plasticity.

• DOI: 10.3389/fnmol.2023.1253669
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Zhang, Yanfeng;Wang, Ting;Cai, Yimei;Cui, Tao;Kuah, Michelle;Vicini, Stefano;Wang, Tingting
• 通讯作者: Wang, Tingting

JOINT for large-scale single-cell RNA-sequencing analysis via soft-clustering and parallel computing.

• DOI: 10.1186/s12864-020-07302-6
• 发表时间: 2021-01-11
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Cui T;Wang T
• 通讯作者: Wang T