Postnatal CCR disruption in MeCP2-defective mice

MeCP2 缺陷小鼠的产后 CCR 破坏

• 批准号: 7641462
• 负责人: CHUN JIANG
• 金额: $ 18.06万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641462
• 关键词: 2 year old; Address; Aerophagy; Affect; Age; Anabolism; Apnea; Arrhythmia; Biological; Birth; Blood gas; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Carbon Dioxide; Catecholamines; Cessation of life; Defect; Development; Disease; Etiology; Family; Feedback; Female; Functional disorder; Genes; Hypercapnia; Hyperpnea; Impairment; Knock-out; Knockout Mice; Lead; Link; Live Birth; Measurement; Methyl-CpG-Binding Protein 2; Modality; Molecular; Molecular Abnormality; Mus; Neurons; Neurotransmitters; Outcome Study; Patients; Play; Proteins; Regulation; Research Design; Rett Syndrome; Role; Severities; Staging; Structure of phrenic nerve; Symptoms; System; Testing; Therapeutic; Wild Type Mouse; autism spectrum disorder; base; design; insight; male; mouse model; novel; postnatal; prevent; protein expression; public health relevance; research study; respiratory; response; sensor

DESCRIPTION (provided by applicant): Rett Syndrome (RTT), a neurodevelopmental disease in the family of Autism Spectrum Disorders, is caused by defects in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), affecting one in every 10,000 live births of females. RTT patients show breathing abnormalities such as episodic respiratory irregularity, breath-holding, apnea, hyperpnea, apneusis, Valsalva breathing, air swallowing, etc. The breathing disorders play a role in the sudden unexplained death and contribute to the abnormal development of the brain. Most of the breathing disturbances are recapitulated in Mecp2- knockout mice in which defects in brainstem respiratory neuronal activity, neurotransmitter systems, protein expression and brain-derived neurotrophic factor have been shown to play a role. Another potential mechanism for the breathing disorders is central CO2 chemoreception (CCR) serving for the feedback regulation of respiratory activity, as disruption of the CCR can lead to severe breathing consequences. Our preliminary studies indicated that the breathing response to a particular level of hypercapnia was impaired in male hemizygous Mecp2-knockout (Mecp2-/Y) mice, accompanying with defects in the several candidate proteins for CO2 chemosensitivity and catecholamine biosynthesis. The CCR defect occurred during maturation and was not seen at age of 4 weeks. We believe that these are important findings, as a novel etiology for the respiratory dysfunction is suggested in the mouse model of RTT. Since the CCR disruption and breathing arrhythmias occur at certain age after birth, detailed studies of the development of the CCR disruption and its molecular and cellular basis may shed insight into the disease and help to formulate effective therapeutic modalities to control breathing disorders in RTT patients. Therefore, we have proposed experiments to address following specific aims: 1) to demonstrate the CCR disruption and its developmental course in Mecp2-/Y mice, and 2) to determine the cellular and molecular abnormalities associated with the development of CCR disruption in Mecp2-/Y mice. Outcome of the studies will advance the understanding of RTT and the design of effective therapeutic modalities to alleviate symptoms and prevent unexpected death of RTT patients. PUBLIC HEALTH RELEVANCE: Rett Syndrome is a neurodevelopmental disease in the Autism Spectrum Disorders. Rett patients show breathing disorders for some unknown reasons, which we hypothesize to be related to the disruption of brainstem CO2 chemoreception. Studies on the development of breathing disorders will lead to information to alleviate breathing disorders and reduce the sudden and unexpected death of the disease.

描述（由申请人提供）：自闭症谱系疾病家族中的一种神经发育疾病RETT综合征（RTT）是由编码X连锁基因编码甲基-CPG结合蛋白2（MECP2）的缺陷引起的，每10,000名活生生的女性每10,000名活生生。 RTT患者表现出呼吸异常，例如情节性呼吸不规则，呼吸呼吸，呼吸暂停，高呼吸，呼吸症，呼吸症，Valsalva呼吸，空气吞咽等。呼吸障碍在突然无法解释的死亡中起作用，并导致大脑异常发育。在MECP2敲除小鼠中概括了大多数呼吸障碍，其中脑干呼吸神经元活性，神经递质系统，蛋白质表达和脑衍生的神经营养因子的缺陷已显示出作用。呼吸障碍的另一个潜在机制是中央二氧化碳化学感受器（CCR）用于反馈调节呼吸活动，因为CCR的破坏会导致严重的呼吸后果。我们的初步研究表明，在男性半合子MECP2-敲除（MECP2-/Y）小鼠中，对特定水平高碳酸盐的呼吸反应受损，并伴随着几种候选蛋白的二氧化碳蛋白的缺陷，用于CO2化学敏感性和性固醇生物合成。 CCR缺陷发生在成熟期间，在4周龄时没有出现。我们认为这些是重要的发现，因为RTT的小鼠模型中建议了呼吸障碍的新型病因。由于CCR的破坏和呼吸心律不齐在出生后的某些年龄发生，因此对CCR破坏的发展及其分子和细胞基础的详细研究可能会洞悉该疾病，并有助于制定有效的治疗方式，以控制RTT患者的呼吸障碍。因此，我们提出了实验来解决以下特定目的：1）证明CCR中断及其在MECP2-/Y小鼠中的发育过程，以及2）确定与MECP2-/Y小鼠中CCR破坏相关的细胞和分子异常。研究的结果将提高对RTT的理解和有效治疗方式的设计，以减轻症状并防止RTT患者意外死亡。 公共卫生相关性：RETT综合征是一种自闭症谱系疾病中的神经发育疾病。 RETT患者出于某些未知原因表现出呼吸障碍，我们假设这与脑干CO2化学感受的破坏有关。关于呼吸障碍发展的研究将导致信息减轻呼吸障碍并减少疾病的突然和意外死亡。