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.

项目摘要/摘要呼吸功能障碍既是阿尔茨海默氏病（AD）的危险因素，也是常见症状，而是该病理基础的分子机制尚不清楚。 AD患者暴露于磷酸化 tau在脑干和宫颈脊髓中的积累，其中包含对呼吸至关重要的神经元临床前阶段，但这些变化对呼吸电路功能的影响尚不清楚。也不知道呼吸功能障碍如何有助于AD病理的发展。在此补充中，我们将检查呼吸电路连通性的变化和随老化和PS19 AD鼠标模型的功能的变化，以便开始了解呼吸障碍与AD进展之间的联系。我们的数据将揭示两个新颖 AD的风险因素和潜在的未来治疗靶标。在AIM 1中，我们将定义呼吸神经元连接性和功能的变化，并在PS19 AD中定义鼠标模型。在AIM 2中，我们将随着时间的流逝确定呼吸神经元种群的转录组和表观遗传变化控制和PS19小鼠以阐明与年龄相关的危险因素和广告诱导的变化。我们将利用在实验室中建立的组合方法作为审讯的父母奖的一部分呼吸电路。我们已经开发了一种结合遗传模型的综合方法，单细胞RNA- 测序，ATAC测序，扩展显微镜，逆行病毒追踪和行为测定，例如整数学，以在体内解决这些问题。我们的方法有可能揭示新的疗法通过调查在AD进程中实施的重要（但已理解的电路）来实现目标。