Respiratory Circuit Dysfunction in Rett Syndrome

雷特综合征的呼吸回路功能障碍

基本信息

批准号：
8533028
负责人：
David M. Katz
金额：
$ 47.61万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533028
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

项目摘要

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.

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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment.

Mecp2 突变小鼠的大脑活动图谱揭示了前脑回路的功能缺陷，包括默认模式网络中的关键节点，这些缺陷可以通过氯胺酮治疗逆转。

DOI：
发表时间：
2012-10-03
期刊：
影响因子：
0
作者：
Kron, Miriam;Howell, C James;Adams, Ian T;Ransbottom, Michael;Christian, Diana;Ogier, Michael;Katz, David M
通讯作者：
Katz, David M

A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.

TrkB 小分子部分激动剂可挽救 Rett 综合征小鼠模型中的 TrkB 磷酸化缺陷并改善呼吸功能。

DOI：
发表时间：
2012-02-01
期刊：
影响因子：
0
作者：
Schmid, Danielle A;Yang, Tao;Ogier, Michael;Adams, Ian;Mirakhur, Yatin;Wang, Qifang;Massa, Stephen M;Longo, Frank M;Katz, David M
通讯作者：
Katz, David M

A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome.

BDNF 环域模拟物可急性逆转雷特综合征小鼠模型行为唤醒期间的自发性呼吸暂停和呼吸异常。

DOI：
发表时间：
2014-09
期刊：
影响因子：
4.3
作者：
Kron, Miriam;Lang, Min;Adams, Ian T;Sceniak, Michael;Longo, Frank;Katz, David M
通讯作者：
Katz, David M

Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.

Mecp2 无效小鼠内侧前额皮质功能性低连接的机制。

DOI：
10.1093/cercor/bhv002
发表时间：
2016-05-01
期刊：
Cerebral cortex
影响因子：
3.7
作者：
M. P. Sceniak;Min Lang;Addison C Enomoto;C. James Howell;Douglas J. Hermes;D. Katz
通讯作者：
D. Katz

Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice.

外源性脑源性神经营养因子可挽救 Mecp2 缺失小鼠的突触功能障碍。