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.

项目摘要/摘要 呼吸是陆生寿命的重要运动功能。发育和遗传疾病 破坏呼吸，例如猝死综合症（SIDS）和RETT综合征，通常患有致命 结果。这可能是由于控制呼吸的神经回路的发展受损。尽管 隔膜肌肉收缩，哺乳动物灵感的驱动力，仅由电动机控制 位于Phrenic运动柱（PMC）中的神经元（MNS），呼吸受复杂的神经回路调节 在后脑。尽管这些电路具有至关重要的重要性，但其分子机制是它们的基础 连通性在很大程度上未知。 我们的实验室表明，HOX5转录因子（TFS）驱动Phrenif Mn连接并调节 特异性细胞粘附分子的表达。我的初步数据表明HOX5表达式有所不同 在后脑呼吸道核中，也许是为了赋予亚型特异性特异性特异性 连接性。在此提案中，我将研究HOX5 TF及其下游效应子的功能 建立呼吸电路连通性。 在AIM 1中，我将评估HOX5基因在呼吸前神经元中如何表达特定连通性的基础 在适当的电路功能所需的呼吸道之间。 在AIM 2中，我将使用遗传操作来确定选择细胞粘附分子如何在下游 HOX5 TF控制呼吸连通性和功能。 我开发了一种结合遗传模型，RNA测序，逆行的综合方法 病毒追踪和电生理学来解决这些问题。了解分子机制 呼吸道发展基础的基础可能会导致患有患者的人的治疗方案 影响呼吸的发育或遗传疾病。