Mechanisms of Congenital Hypoventilation

先天性通气不足的机制

• 批准号: 9486593
• 负责人: CATHERINE CZEISLER
• 金额: $ 4.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9486593
• 关键词: Ablation; Address; Affect; Alpha Cell; Anatomy; Apnea; Astrocytes; Autonomic nervous system; Birth; Brain Stem; Breathing; Carbon Dioxide; Cell Communication; Cell Nucleus; Child; Data; Development; Developmental Process; Diffuse; Discipline; Disease; Dominant-Negative Mutation; Embryo; Environmental air flow; Event; Foundations; Functional disorder; Future; Gene Mutation; Genetic Models; Health; Homeobox Genes; Human; Hypercapnia; Hypercapnic respiratory failure; Impairment; Intervention; Intervention Studies; Knowledge; Link; Literature; Mammals; Mediator of activation protein; Mission; Morbidity - disease rate; Mus; Mutation; Neuroglia; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Perinatal; Pharmacology; Phenotype; Physiological; Population; Premature Infant; Premature Mortality; Process; Public Health; Rare Diseases; Reagent; Regulation; Research; Respiration; Respiratory Center; Respiratory Process; Risk; Secondary to; Stem cells; Structure of area postrema; System; Systems Development; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Work; attenuation; base; clinical phenotype; congenital central hypoventilation syndrome; design; developmental disease; hindbrain; human disease; improved; innovation; insight; mortality; multidisciplinary; nerve supply; neural circuit; neuromechanism; novel; polyalanine; postnatal; premature; progenitor; public health relevance; respiratory; selective expression; therapy design; tool

 DESCRIPTION (provided by applicant): Incomplete respiratory neuron maturation causes significant morbidity during the perinatal period, yet the mechanisms by which respiratory neuron maturation occurs during this vulnerable time window is not understood. Thus, there is a critical need to identify these basic neural mechanisms of perinatal respiratory control. The objectives of the proposed research are to elucidate developmental processes of respiratory neuron network maturation and to identify brainstem respiratory centers/circuits necessary for perinatal breathing. The central hypothesis is that hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal, and post-natal periods in mammals, and that developmental abnormalities in neuronal and glial maturation contribute to the pathophysiology of autonomic respiratory neuron dysfunction. The proposed research is inspired by our group's findings of Central Congenital Hypoventilation Syndrome (CCHS), a rare human disorder characterized by an inability to sense CO2 and which is linked to PHOX2B poly-alanine repeat and non-polyalanine repeat (NPARM) mutations. The rationale for the proposed research is that the lack of a basic fundamental understanding of which autonomic neural circuits are required for perinatal breathing represents a barrier to the ultimate implementation of interventions aimed at improving morbidity for premature infants. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the extent to which selective expression of a dominant negative NPARM-PHOX2B mutation regulates perinatal chemosensation-induced respiratory drive, 2) Determine which brainstem circuits are lost in NPARM-CCHS, and 3) Determine the extent to which selected ablation of brainstem astrocyte population promote congenital hypoventilation. Under the first aim, we will test the effects on ventilation control and brainstem anatomy after targeted brainstem expression of a dominant negative NPARM PHOX2B mutation using an already proven conditional transgenic mouse approach. In the second aim, we will combine an innovative transgenic approach to identify which brainstem circuits are lost in congenital hypoventilation. In the third aim, we will determine the extent to which neuronal-glial interaction are necessary for appropriate autonomic respiratory control in the perinatal and post-natal period. The approach is innovative because it uses novel and validated tools, techniques, and reagents from distinct disciplines that allow us to address previously unanswerable questions. The proposed research is significant, because it is expected to vertically advance and expand understanding of which neuronal-glial circuits are required for proper control of autonomic regulation of breathing at birth. The tools and basic knowledge gained from these studies will form the foundation of future studies where interventions to improve autonomic respiratory neuron function in premature babies are designed and validated.

 描述（由申请人提供）：呼吸神经元不完全成熟导致围产期的显著发病率，但呼吸神经元成熟在此脆弱时间窗内发生的机制尚不清楚。因此，有一个关键的需要，以确定这些基本的神经机制，围产期呼吸控制。拟议的研究的目的是阐明呼吸神经元网络成熟的发育过程，并确定脑干呼吸中心/电路围产期呼吸所需的。中心假设是，后脑呼吸神经元网络在哺乳动物的胚胎晚期，围产期和出生后时期经历关键的发育成熟，神经元和神经胶质成熟的发育异常有助于自主呼吸神经元功能障碍的病理生理学。这项研究的灵感来自于我们小组对中枢性先天性换气不足综合征（CCHS）的发现，这是一种罕见的人类疾病，其特征是无法感知CO2，并且与PHOX 2B多聚丙氨酸重复和非多聚丙氨酸重复（NPARM）突变有关。提出这项研究的理由是，缺乏对围产期呼吸所需的自主神经回路的基本了解，这是最终实现呼吸功能的障碍。 实施旨在降低早产儿发病率的干预措施。在强有力的初步数据的指导下，将通过追求三个特定目标来检验该假设：1）确定显性阴性NPARM-PHOX 2B突变的选择性表达调节围产期化学敏感诱导的呼吸驱动的程度，2）确定NPARM-CCHS中哪些脑干回路丢失，3）确定脑干星形胶质细胞群体的选择性消融促进先天性通气不足的程度。在第一个目标下，我们将使用已经证明的条件性转基因小鼠方法测试显性阴性NPARM PHOX 2B突变的靶向脑干表达后对通气控制和脑干解剖结构的影响。在第二个目标中，我们将结合联合收割机一种创新的转基因方法，以确定哪些脑干回路在先天性通气不足中丢失。在第三个目标中，我们将确定在围产期和出生后时期，神经元-神经胶质相互作用对于适当的自主呼吸控制是必要的。这种方法是创新的，因为它使用了来自不同学科的新颖且经过验证的工具、技术和试剂，使我们能够解决以前无法回答的问题。这项研究意义重大，因为它有望垂直推进和扩展对出生时呼吸自主调节的正确控制所需神经元-胶质细胞回路的理解。从这些研究中获得的工具和基本知识将成为未来研究的基础，在这些研究中，设计和验证改善早产儿自主呼吸神经元功能的干预措施。