Molecular Mechanisms of Respiratory Circuit Connectivity

呼吸回路连接的分子机制

• 批准号: 10612392
• 负责人: Matthew Thomas Moore
• 金额: $ 3.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612392
• 关键词: Address; Affect; Air; Amyotrophic Lateral Sclerosis; Automobile Driving; Behavior; Bilateral; Birth; Breathing; Cadherins; Cell Adhesion Molecules; Cell Nucleus; Characteristics; Complex; Data; Development; Disease; Electrophysiology (science); Embryo; Exhibits; Family; Gene Expression; Genes; Genetic Diseases; Genetic Models; Homeobox; Homeodomain Proteins; Impairment; In Situ Hybridization; Label; Life; Mammals; Medulla Oblongata; Methodology; Molecular; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Nervous System; Neurons; Plethysmography; Population; Respiration; Respiration Disorders; Respiratory Diaphragm; Respiratory distress; Respiratory physiology; Rest; Retina; Rett Syndrome; Role; Signal Transduction; Specific qualifier value; Spinal Cord; Structure of phrenic nerve; Sudden infant death syndrome; Symptoms; Synaptophysin; Techniques; Testing; Tidal Volume; Transgenes; Viral; Visual; conditional knockout; developmental disease; differential expression; driving force; experimental study; genetic manipulation; hindbrain; improved; mouse model; neural; neural circuit; neurodevelopment; new therapeutic target; novel; preBotzinger complex; prevent; progenitor; respiratory; synaptogenesis; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Breathing is an essential motor function for terrestrial life. Developmental and genetic disorders that disrupt breathing, such as sudden infant death syndrome (SIDS) and Rett syndrome, often have fatal consequences. This is likely due to the impaired development of neural circuits that control breathing. While diaphragm muscle contractions, the driving force for inspiration in mammals, are controlled solely by motor neurons (MNs) located in the phrenic motor column (PMC), respiration is regulated by complex neural circuitry in the hindbrain. Despite the critical importance of these circuits, the molecular mechanisms that underlie their connectivity are largely unknown. Our lab has shown that Hox5 transcription factors (TFs) drive phrenic MN connectivity and regulate the expression of phrenic-specific cell adhesion molecules. My preliminary data indicate that Hox5 expression varies across hindbrain respiratory nuclei, perhaps acting to confer subtype-specific characteristics required for connectivity. In this proposal, I will investigate the function of Hox5 TFs and their downstream effectors in establishing respiratory circuit connectivity. In Aim 1, I will assess how Hox5 gene expression in respiratory premotor neurons underlies specific connectivity between respiratory populations required for proper circuit function. In Aim 2, I will use genetic manipulations to determine how select cell adhesion molecules act downstream of Hox5 TFs to control respiratory connectivity and function. I have developed an integrative methodology combining genetic models, RNA-sequencing, retrograde viral tracing, and electrophysiology to address these questions. Understanding the molecular mechanisms that underlie respiratory circuit development could lead to improved treatment options for those suffering from developmental or genetic diseases that affect breathing.

项目概要/摘要 呼吸是陆地生命的重要运动功能。发育和遗传疾病 呼吸紊乱，例如婴儿猝死综合症（SIDS）和雷特综合症，通常会致命 结果。这可能是由于控制呼吸的神经回路发育受损所致。尽管 膈肌收缩是哺乳动物吸气的驱动力，仅由电机控制 神经元 (MN) 位于膈运动柱 (PMC) 中，呼吸由复杂的神经回路调节 在后脑中。尽管这些电路至关重要，但其背后的分子机制 连接性很大程度上是未知的。 我们的实验室表明 Hox5 转录因子 (TF) 驱动膈 MN 连接并调节 膈特异性细胞粘附分子的表达。我的初步数据表明 Hox5 表达有所不同 穿过后脑呼吸核，可能起到赋予亚型所需的特定特征的作用 连接性。在本提案中，我将研究 Hox5 TF 及其下游效应器的功能 建立呼吸回路连接。 在目标 1 中，我将评估呼吸前运动神经元中的 Hox5 基因表达如何构成特定连接的基础 正常回路功能所需的呼吸群体之间的关系。 在目标 2 中，我将使用基因操作来确定选择的细胞粘附分子如何在下游发挥作用 Hox5 TF 控制呼吸连接和功能。 我开发了一种综合方法，结合了遗传模型、RNA 测序、逆行 病毒追踪和电生理学可以解决这些问题。了解其分子机制 呼吸回路发展的基础可能会改善患有以下疾病的患者的治疗选择 影响呼吸的发育或遗传疾病。