Respiratory Circuit Dysfunction in Rett Syndrome

雷特综合征的呼吸回路功能障碍

• 批准号: 8184609
• 负责人: David M. Katz
• 金额: $ 38.69万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184609
• 关键词: Action Potentials; Address; Affect; Agonist; Alleles; Behavioral; Birth; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Cell Nucleus; Cell physiology; Cells; Cognitive; Complex; Defect; Development; Disease; Economic Inflation; Electric Stimulation; Equilibrium; Exhibits; Female; Fiber; Fostering; Functional disorder; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genetically Engineered Mouse; Human; Hyperventilation; Hypoxia; Immediate-Early Genes; In Vitro; Interneurons; Knockout Mice; Knowledge; Life; Light; Lung; Maps; Mediating; Methods; Motor; Mus; Mutant Strains Mice; Mutate; Mutation; Neurologic Deficit; Neurologic Dysfunctions; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus solitarius; Pathway interactions; Patients; Plethysmography; Pontine structure; Population; Preparation; Proteins; Reflex action; Research; Respiratory physiology; Rest; Rett Syndrome; Role; Severities; Severity of illness; Signal Transduction; Signaling Molecule; Site; Slice; Structure; Symptoms; Synapses; Testing; Therapeutic; autism spectrum disorder; base; design; electrical property; in vivo; innovation; insight; interdisciplinary approach; lung hypoxia; mouse model; mutant; neurochemistry; neuromechanism; neuronal excitability; neuronal patterning; novel strategies; novel therapeutic intervention; novel therapeutics; patch clamp; respiratory; respiratory reflex; response; small molecule; synaptic function; transmission process

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a complex Autism Spectrum Disorder (ASD) that is caused by mutations in the MECP2 gene and affects approximately 1 in 10,000 live female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and up to 25% of RTT patients may die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders, or any other neurologic deficits in RTT. Our understanding of neural mechanisms that underlie respiratory dysfunction in RTT is hampered by the fact that we still know little about how loss of MECP2 affects neuronal and/or synaptic function in specific brainstem respiratory circuits. Therefore, the proposed research takes a multidisciplinary approach to define how genetic loss of MECP2 disrupts respiratory control, focusing on modulation of excitatory-inhibitory balance in key respiratory reflex pathways in the brainstem using a well-defined mouse model of the disease. Electrophysiological methods will be used in brainstem slices in vitro to test the hypothesis that increased excitability at primary afferent synapses regulating reflex responses to hypoxia and lung inflation contributes to respiratory circuit dysfunction in RTT and to define underlying mechanisms. We will also examine how deficits in Brain Derived Neurotrophic Factor (BDNF), a key neuronal signaling molecule whose expression is severely decreased in RTT, contribute to synaptic dysfunction, as well as the ability of molecules that enhance BDNF signaling to restore normal function in RTT mice in vitro and in vivo. In addition, we will use Fos immunostaining to map sites throughout the brainstem respiratory network at which neuronal and/or synaptic function is disrupted in vivo. Finally, we will examine how a common polymorphism in the human BDNF gene, Val66Met-BDNF, influences the severity of respiratory symptoms and the therapeutic response to BDNF- targeted therapies in mice. The proposed research aims to define mechanisms that underlie respiratory dysfunction in RTT using innovative experimental approaches and mouse models. By focusing on synaptic excitability, and BDNF-mediated signaling in particular, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders in RTT. Moreover, it is hoped that insights obtained from analysis of circuit dysfunction in RTT will be broadly applicable to ASDs as a whole. PUBLIC HEALTH RELEVANCE: The proposed research seeks to define mechanisms that underlie breathing disorders in Rett syndrome (RTT), a devastating Autism Spectrum Disorder affecting approximately 1 in 10,000 female births worldwide. RTT patients suffer from uncontrollable periods of hyperventilation and breath-holding and up to 25% die prematurely of cardiorespiratory complications. The proposed studies will use mouse models of RTT to identify defects in nerve cell function that cause abnormal breathing in this disease and to develop potential new therapeutic approaches.

描述（由申请人提供）：雷特综合征 (RTT) 是一种复杂的自闭症谱系障碍 (ASD)，由 MECP2 基因突变引起，影响全球大约万分之一的活产女婴。除了认知、运动和行为缺陷之外，RTT 最严重的身体衰弱后果之一是呼吸控制的严重破坏，高达 25% 的 RTT 患者可能因心肺并发症过早死亡。目前，尚无针对呼吸障碍或 RTT 中任何其他神经系统缺陷的治疗方法。我们对 RTT 呼吸功能障碍背后的神经机制的理解受到以下事实的阻碍：我们仍然对 MECP2 的缺失如何影响特定脑干呼吸回路中的神经元和/或突触功能知之甚少。因此，拟议的研究采用多学科方法来定义 MECP2 的遗传丢失如何破坏呼吸控制，重点是使用明确的疾病小鼠模型来调节脑干关键呼吸反射途径的兴奋性抑制平衡。电生理学方法将用于体外脑干切片，以测试调节对缺氧和肺充气的反射反应的初级传入突触兴奋性增加导致 RTT 中呼吸回路功能障碍的假设，并确定潜在机制。我们还将研究脑源性神经营养因子（BDNF）的缺陷如何导致突触功能障碍，以及增强 BDNF 信号传导的分子恢复 RTT 中正常功能的能力。BDNF 是一种关键的神经元信号分子，其表达在 RTT 中严重降低。小鼠体外和体内。此外，我们将使用 Fos 免疫染色来绘制整个脑干呼吸网络中神经元和/或突触功能在体内被破坏的位点。最后，我们将研究人类 BDNF 基因中常见的多态性 Val66Met-BDNF 如何影响小鼠呼吸道症状的严重程度以及对 BDNF 靶向治疗的治疗反应。拟议的研究旨在利用创新的实验方法和小鼠模型来确定 RTT 呼吸功能障碍的机制。通过关注突触兴奋性，特别是 BDNF 介导的信号传导，希望这些研究能够促进 RTT 呼吸障碍新治疗策略的开发。此外，希望从 RTT 中的电路功能障碍分析中获得的见解能够广泛适用于整个 ASD。 公共健康相关性：拟议的研究旨在确定雷特综合征 (RTT) 呼吸障碍的机制，这是一种毁灭性的自闭症谱系障碍，影响全球大约万分之一的女性新生儿。 RTT 患者患有无法控制的过度换气和屏气期，高达 25% 的患者因心肺并发症过早死亡。拟议的研究将使用 RTT 小鼠模型来识别导致这种疾病呼吸异常的神经细胞功能缺陷，并开发潜在的新治疗方法。