Genetic Control of Phrenic Motor Neuron Development and Maintenance

膈运动神经元发育和维持的遗传控制

• 批准号: 10711755
• 负责人: Polyxeni Philippidou
• 金额: $ 32.38万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10711755
• 关键词: ARHGEF5 gene; ATAC-seq; Address; Adult; Age; Aging; Air; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anatomy; Animals; Award; Behavior; Behavioral Assay; Biological Assay; Blinded; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Cervical spinal cord structure; Chromatin; Collaborations; Consult; Contracts; Control Animal; DLG4 gene; Data; Data Set; Development; Disease; Disease Progression; Early identification; Electrophysiology (science); Embryo; Epigenetic Process; Exhibits; Exons; Exposure to; Female; Fiji; Fluorescence-Activated Cell Sorting; Frequencies; Future; GTP-Binding Proteins; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic; Genetic Models; Genetic Recombination; Genetic Transcription; Genomics; Genotype; Graph; Hypercapnia; Hypoxia; Image; Inhalation; Injections; Intervention; Label; Letters; Libraries; Link; LoxP-flanked allele; Maintenance; Maps; Measures; Mediating; Methodology; Methods; Microscopy; Mind; Molecular; Motor; Mouse Strains; Mus; Muscle; Nerve; Neurofibrillary Tangles; Neurons; Oxygen; Paralysed; Parents; Pathology; Plethysmography; Population; Positioning Attribute; Predisposition; Preparation; Property; Protocols documentation; Rabies virus; Reporter; Respiration Disorders; Respiratory Diaphragm; Respiratory Signs and Symptoms; Rest; Risk Factors; Same-sex; Site; Sleep Apnea Syndromes; Spinal Cord; Spottings; Stains; Stress; Symptoms; Synapses; Terminator Codon; Testing; Tidal Volume; Time; Transposase; Universities; Viral; Virus; Visualization; Vomiting; Weight; Work; age related; cDNA Library; combinatorial; common symptom; distributed data; experience; experimental study; genetic approach; gephyrin; glycoprotein G; high resolution imaging; hyperphosphorylated tau; imaging software; in vivo; insight; male; mature animal; motor deficit; motor neuron development; mouse model; new therapeutic target; novel; postnatal; postsynaptic; pre-clinical; presynaptic; protein expression; rabies viral tracing; recruit; respiratory; respiratory challenge; sex; single-cell RNA sequencing; tau aggregation; tau-1; therapeutic target; timeline; tool; transcriptome; transcriptome sequencing; transcriptomics; ventilation

Project Summary/Abstract Respiratory dysfunction is both a risk factor and a common symptom in Alzheimer’s disease (AD), but the molecular mechanisms that underlie this pathology are not well understood. AD patients exhibit phosphorylated tau accumulation in the brainstem and cervical spinal cord, which contain neurons critical for breathing, at preclinical stages but the impact of these changes on respiratory circuit function is not clear. It is also not known how respiratory dysfunction contributes to the progression of AD pathology. In this supplement, we will examine changes in respiratory circuit connectivity and function with aging and in the PS19 AD mouse model, in order to begin to understand the link between respiratory dysfunction and AD progression. Our data will reveal both novel risk factors and potential future therapeutic targets for AD. In Aim 1 we will define changes in respiratory neuron connectivity and function with aging and in the PS19 AD mouse model. In Aim 2 we will determine transcriptomic and epigenetic changes in respiratory neuron populations over time in control and PS19 mice to elucidate age-related risk factors and AD-induced changes. We will utilize a combinatorial approach established in our lab as part of the parent award for interrogating respiratory circuits. We have developed an integrative methodology combining genetic models, single-cell RNA- sequencing, ATAC-sequencing, expansion microscopy, retrograde viral tracing, and behavioral assays, such as plethysmography, to address these questions in vivo. Our approach has the potential to reveal novel therapeutic targets by investigating a vital, yet understudied, circuit implicated in AD progression.

项目总结/摘要 呼吸功能障碍是阿尔茨海默病（AD）的危险因素和常见症状，但 这种病理学的分子机制还不清楚。AD患者表现出磷酸化 tau蛋白在脑干和颈脊髓中的积累，其中含有对呼吸至关重要的神经元， 临床前阶段，但这些变化对呼吸回路功能的影响尚不清楚。尚不清楚 呼吸功能障碍如何促进AD病理学的进展。在本补充中，我们将研究 呼吸回路连通性和功能随年龄增长的变化以及PS19 AD小鼠模型， 开始了解呼吸功能障碍和AD进展之间的联系。我们的数据将揭示 AD的危险因素和潜在的未来治疗靶点。 在目标1中，我们将定义呼吸神经元连接和功能随衰老的变化以及PS19 AD中的变化。 小鼠模型 在目标2中，我们将确定呼吸神经元群体随时间的转录组学和表观遗传学变化， 对照和PS19小鼠，以阐明年龄相关的风险因素和AD诱导的变化。 我们将利用我们实验室建立的组合方法，作为询问父母奖励的一部分 呼吸回路我们开发了一种综合方法，将遗传模型、单细胞RNA- 测序、ATAC测序、扩增显微术、逆行病毒追踪和行为测定，例如 体积描记术，以解决这些问题在体内。我们的方法有可能揭示新的治疗方法， 通过研究一个重要的，但研究不足的，涉及AD进展的电路。