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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要/摘要呼吸功能障碍既是阿尔茨海默病 (AD) 的危险因素，也是常见症状，但 AD 患者表现出磷酸化的分子机制尚不清楚。 tau 蛋白在脑干和颈脊髓中积累，这些神经元对呼吸至关重要临床前阶段，但这些变化对呼吸回路功能的影响尚不清楚。在本补充材料中，我们将研究呼吸功能障碍如何导致 AD 病理的进展。在 PS19 AD 小鼠模型中，呼吸回路连接性和功能随衰老而变化，以便开始了解呼吸功能障碍与 AD 进展之间的联系，我们的数据将揭示这两种新颖的现象。 AD 的危险因素和未来潜在的治疗目标。在目标 1 中，我们将定义呼吸神经元连接和功能随衰老和 PS19 AD 的变化鼠标模型。在目标 2 中，我们将确定呼吸神经元群体随时间的转录组和表观遗传变化对照小鼠和 PS19 小鼠，以阐明与年龄相关的危险因素和 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家长奖励的一部分来询问我们开发了一种结合遗传模型、单细胞 RNA 的综合方法。测序、ATAC 测序、扩增显微镜、逆行病毒追踪和行为测定，例如体积描记法，在体内解决这些问题，我们的方法有可能揭示新的治疗方法。通过调查与 AD 进展有关的重要但尚未充分研究的回路来实现目标。