Postnatal CCR disruption in MeCP2-defective mice

MeCP2 缺陷小鼠的产后 CCR 破坏

• 批准号: 7821458
• 负责人: CHUN JIANG
• 金额: $ 21.46万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7821458
• 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）：Rett综合征（RTT）是自闭症谱系障碍家族中的一种神经发育疾病，由编码甲基CpG结合蛋白2（MeCP 2）的X连锁基因缺陷引起，每10，000例活产女性中就有一例受影响。RTT患者表现出呼吸异常，如间歇性呼吸不规则、屏气、呼吸暂停、呼吸过度、呼吸暂停、Valsalva呼吸、空气吞咽等。呼吸障碍在不明原因的猝死中起作用，并导致大脑发育异常。大多数呼吸障碍在Mecp 2基因敲除小鼠中重现，其中脑干呼吸神经元活性、神经递质系统、蛋白质表达和脑源性神经营养因子的缺陷已被证明起作用。呼吸障碍的另一个潜在机制是中枢CO2化学感受（CCR），其用于呼吸活动的反馈调节，因为CCR的中断可导致严重的呼吸后果。我们的初步研究表明，在雄性半合子Mecp 2基因敲除（Mecp 2-/Y）小鼠中，对特定水平的高碳酸血症的呼吸反应受损，伴随着CO2化学敏感性和儿茶酚胺生物合成的几种候选蛋白质的缺陷。CCR缺陷发生在成熟过程中，在4周龄时未见。我们认为这些是重要的发现，因为在RTT小鼠模型中提出了呼吸功能障碍的新病因。由于CCR中断和呼吸心律失常发生在出生后的一定年龄，CCR中断的发展及其分子和细胞基础的详细研究可能会揭示疾病，并有助于制定有效的治疗方法来控制RTT患者的呼吸障碍。因此，我们提出了以下具体目的的实验：1）证明CCR破坏及其在Mecp 2-/Y小鼠中的发展过程，和2）确定与Mecp 2-/Y小鼠中CCR破坏的发展相关的细胞和分子异常。这些研究的结果将促进对RTT的理解，并设计有效的治疗方式，以减轻症状，防止RTT患者的意外死亡。 公共卫生相关性：雷特综合征是自闭症谱系障碍中的一种神经发育疾病。Rett患者因某些未知原因出现呼吸障碍，我们假设这与脑干CO2化学感受性的破坏有关。对呼吸障碍发展的研究将导致缓解呼吸障碍和减少疾病的突然和意外死亡的信息。

项目成果

Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.

• DOI: 10.1016/j.bbrc.2010.02.156
• 发表时间: 2010-04-02
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Zhang, Xiaoli;Su, Junda;Rojas, Asheebo;Jiang, Chun
• 通讯作者: Jiang, Chun

Breathing abnormalities in a female mouse model of Rett syndrome.

• DOI: 10.1007/s12576-015-0384-5
• 发表时间: 2015-09
• 期刊: The journal of physiological sciences : JPS
• 作者: Johnson CM;Cui N;Zhong W;Oginsky MF;Jiang C
• 通讯作者: Jiang C

Molecular basis and structural insight of vascular K(ATP) channel gating by S-glutathionylation.

S-谷胱甘肽化血管 K(ATP) 通道门控的分子基础和结构见解。

• DOI: 10.1074/jbc.m110.195123
• 发表时间: 2011
• 期刊: The Journal of biological chemistry
• 作者: Yang,Yang;Shi,Weiwei;Chen,Xianfeng;Cui,Ningren;Konduru,AnuhyaS;Shi,Yun;Trower,TimothyC;Zhang,Shuang;Jiang,Chun
• 通讯作者: Jiang,Chun