Homeostatic Stabilization of Neural Function in Health and Disease

健康和疾病中神经功能的稳态稳定

• 批准号: 9152175
• 负责人: GRAEME W DAVIS
• 金额: $ 101万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152175
• 关键词: Aging; Animals; Autistic Disorder; Biological Models; Brain; Brain Diseases; Calcium; Data; Disease; Disease model; Endoplasmic Reticulum; Epilepsy; Foundations; Genetic; Goals; Health; Immune signaling; Impairment; Learning; Life; Link; Memory; Modeling; Molecular; Nerve Degeneration; Nervous system structure; Neurological Models; Neurons; Neurophysiology - biologic function; Neurosciences; Peripheral Nervous System; Phosphotransferases; Property; Reproducibility; Role; Signal Pathway; Signal Transduction; Synapses; System; Theoretical model; Work; experimental study; insight; interest; nervous system disorder; neuroregulation; neurotransmission; neurotransmitter release; next generation; novel; presynaptic; relating to nervous system; sensor; theories

PROJECT SUMMARY/ABSTRACT The brain is astonishing in its complexity and capacity for change. It seems certain that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. It is now clear that homeostatic signaling systems function throughout the central and peripheral nervous systems to stabilize neural function throughout life. As a consequence, it is widely believed that impaired or maladaptive homeostatic signaling will be directly relevant to the cause and progression of neurological diseases that include epilepsy, autism and neurodegeneration. However, despite widespread evidence for the homeostatic control of neural function throughout the animal kingdom and implicit relevance to disease and aging, very little is known about the underlying mechanisms. The field of homeostatic plasticity is wide open for exploration and the potential for transformative advancement in cellular and molecular neuroscience is tremendous. We are leading the rapidly emerging field of homeostatic plasticity, harnessing the power of unbiased model system genetics to identify and characterize fundamentally new cellular and molecular mechanisms of homeostatic signaling in the nervous system. Our experiments will define many of the first signaling pathways identified to participate in the homeostatic signaling systems that control presynaptic neurotransmitter release and intrinsic neural excitability. Our approaches have uncovered a novel activity of the innate immune signaling system, new trans-synaptic signaling pathways, novel calcium sensors, novel neuronal kinase signaling systems, new roles for the presynaptic endoplasmic reticulum and tangible links to neurological disease. As such, our data will provide a foundation for exploring the impact homeostatic plasticity in mammalian models of neurological disease including epilepsy, autism and neurodegeneration. Our data will also directly impact current theories and models of homeostatic signaling. Current theoretical models have captured widespread interest. Molecular insight will provide important new ideas and new constraints for the next generation of theoretical models of homeostatic plasticity, learning and memory.

项目摘要/摘要 大脑的复杂性和变化能力令人惊讶。似乎可以肯定的是驱动的可塑性 我们学习和记住的能力只有在原本稳定，可重复的背景下才有意义 可预测的基线神经功能。现在很明显，体内稳态信号系统在整个过程中起作用 中央和周围神经系统，以稳定一生的神经功能。结果，是 人们普遍认为，受损或适应不良的稳态信号将与原因直接相关 包括癫痫，自闭症和神经退行性的神经系统疾病的进展。但是，尽管如此 整个动物王国中神经功能的稳态控制和隐式的广泛证据 与疾病和衰老有关，对基本机制知之甚少。体内平衡领域 可塑性很广泛，可用于探索，并在细胞和 分子神经科学是巨大的。我们正在领导稳态可塑性的快速新兴领域， 利用公正的模型系统遗传学的力量来识别和表征从根本上进行新的 神经系统中稳态信号传导的细胞和分子机制。我们的实验会 定义许多确定参与体内稳态信号系统的第一个信号通路 控制突触前神经递质释放和内在的神经兴奋性。我们的方法已经发现了 先天免疫信号系统的新活性，新的跨突触信号通路，新钙 传感器，新型神经元激酶信号系统，突触前内质网和的新作用 与神经疾病的切实联系。因此，我们的数据将为探索影响提供基础 哺乳动物模型的神经系统疾病模型的稳态可塑性，包括癫痫，自闭症和 神经变性。我们的数据还将直接影响稳态信号的当前理论和模型。 当前的理论模型引起了广泛的兴趣。分子见解将提供重要的新 稳态可塑性，学习和下一代理论模型的思想和新约束 记忆。