How discrete homeostatic signals stabilize synapse function across time

离散稳态信号如何随时间稳定突触功能

• 批准号: 10706581
• 负责人: CARL ANDREW FRANK
• 金额: $ 38.97万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706581
• 关键词: Acute; Address; Ataxia; Binding; Biochemistry; Biological Models; Bone Morphogenetic Proteins; Buffers; Calcium; Chaperone Gene; Chemosensitization; Chronic; Data; Depressed mood; Development; Disease; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Engineering; Epilepsy; Event; Exhibits; Fibroblast Growth Factor Receptors; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Screening; Glutamate Receptor; Goals; Health; Homeostasis; Hour; Image; Impairment; Knowledge; Life; Link; Maintenance; Mediating; Methods; Migraine; Modality; Modeling; Molecular; Molecular Chaperones; Monitor; Motor Neurons; Muscle; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neuromuscular Junction; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitter Receptor; Outcome; Output; Pathway interactions; Peptide Signal Sequences; Pharmacology; Phase; Physiological; Process; Property; Puncture procedure; Research; Research Design; Science; Semaphorins; Signal Induction; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Spermine; Stress; Synapses; Synaptic plasticity; System; Testing; Time; Work; effective therapy; follow-up; improved; inhibitor; loss of function; nervous system disorder; neurotransmission; pharmacologic; presynaptic; receptor function; synaptic function; tool; transmission process

PROJECT SUMMARY Background and Objectives: Synapses and circuits possess a robust capacity for keeping their outputs stable. Using the Drosophila melanogaster neuromuscular junction (NMJ) as a model synapse, many labs have recently identified dozens of signaling molecules and processes that stabilize synapse function through a non-Hebbian form of homeostatic neuroplasticity called presynaptic homeostatic potentiation (PHP). These findings offer a rich reservoir for discovery science, but at this point we have little understanding of how dozens of discrete homeostatic signaling molecules integrate into coherent system that stabilizes synapse function over time. The objective of this proposal is to solve that problem combining genetics, pharmacology, imaging, biochemistry, and electrophysiology. Ultimately, improved knowledge about homeostatic forms of synaptic plasticity could lead to a better understanding of neurological disorders that occur when synapse stability is lost. Specific Aims and Research Design: This project has two specific aims. We know that PHP at the Drosophila NMJ can be acutely induced in minutes and then chronically maintained for days. The first aim is to define a sequence of events that occurs during the opening minutes of PHP induction. For this aim, we take advantage of a serendipitous finding from a genetic screen: impaired chaperone function in the muscle slows PHP signaling. Using this genetic tool we will delineate an order of processes that occurs as the muscle signals to the nerve and potentiates release. For the second aim, we developed a new pharmacological approach to monitor the transition periods between induction, acute expression, and long-term maintenance of PHP. We will apply this new method to characterize about 25 known genetic conditions that impact the sustained maintenance of PHP. We expect to define distinct PHP signaling modalities. Between our aims, the expected outcome is a model of how a synapse can sustain homeostatic function by integrating multiple signals across phases of time. Health Relatedness: Neurological disorders like epilepsy, ataxia, and migraine are associated with unstable neuronal function. Understanding how synapses work to maintain stability on a molecular level could have pro- found implications for disorders with underlying neuronal instabilities. Yet the signaling events that tightly control levels of synaptic output are poorly understood. The tractable Drosophila NMJ employs homoestatic strategies to stabilize synapse function – such as altering levels of presynaptic calcium influx – that are shared by mammalian central synapses. Taking advantage of the molecular and genetic tools offered by the NMJ promises to shed light on universally conserved mechanisms of how synapses maintain stable function throughout life.

项目摘要 背景和目标：突触和电路具有保持其输出稳定的强大能力。 将果蝇Melanogaster神经肌肉连接（NMJ）作为模型突触，最近许多实验室都有 鉴定出数十个信号分子和通过非赫比亚人稳定突触功能的过程 稳态神经塑性的形式称为突触前体内增强（PHP）。这些发现提供了 富裕的发现科学水库，但是在这一点上，我们对数十个离散的方式几乎没有理解 稳态信号分子整合到相干系统中，随着时间的推移稳定突触功能。这 该建议的目的是解决结合遗传学，药理学，成像，生物化学和 电生理学。最终，对稳态形式的突触可塑性的知识的提高可能导致 在失去突触稳定性时会更好地理解发生的神经系统疾病。 具体目标和研究设计：该项目具有两个特定的目的。我们知道果蝇的PHP NMJ可以在几分钟内敏锐地诱导，然后长期保持几天。第一个目的是定义 在PHP诱导的开放时间内发生的事件顺序。为此，我们利用 从遗传筛选中发现的偶然发现：肌肉中的伴侣功能受损会减慢PHP信号传导。 使用这种遗传工具，我们将描述作为神经肌肉信号的过程顺序 潜力释放。对于第二个目标，我们开发了一种新的药物方法来监视 诱导，急性表达和PHP的长期维持之间的过渡期。我们将应用此 表征大约25种已知遗传条件的新方法，这些遗传条件会影响PHP的持续维持。 我们期望定义不同的PHP信号传导方式。在我们的目标之间，预期的结果是 突触如何通过跨时阶段整合多个信号来维持稳态功能。 健康相关性：癫痫，共济失调和偏头痛等神经系统疾病与不稳定有关 神经元功能。了解突触如何在分子水平上保持稳定性的工作方式可能会产生 发现对潜在神经元不稳定性的疾病的影响。然而，紧密控制的信号事件 突触输出水平知之甚少。可处理的果蝇NMJ员工的同义策略 为了稳定突触功能（例如改变突触前钙影响的水平），这些功能由 哺乳动物中央突触。利用NMJ承诺提供的分子和遗传工具 阐明了普遍构成突触如何保持稳定功能的机制。