Analysis of MeCP2 function in neural crest derivatives

神经嵴衍生物中 MeCP2 功能分析

• 批准号: 8102975
• 负责人: Christopher S Ward
• 金额: $ 3.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102975
• 关键词: Address; Affect; Animals; Apnea; Autonomic Dysfunction; Autonomic nervous system; Bradycardia; Breathing; Cardiac; Cause of Death; Cessation of life; Clinical; Constipation; Data; Disease; Encephalopathies; Excision; Ganglia; Gene Mutation; Genes; Genetic Techniques; Goals; Heart Rate; Hyperventilation; Individual; Life; Limb structure; Link; Longevity; Methyl-CpG-Binding Protein 2; Mus; Mutation; Neural Crest; Neurons; Pathogenesis; Patients; Pattern; Phenotype; Population; Quality of life; Regulation; Research; Research Personnel; Rett Syndrome; Role; Sympathetic Ganglia; System; Testing; Tetracyclines; Therapeutic; Tissues; Transgenic Organisms; Tyrosine 3-Monooxygenase; Work; boys; gastrointestinal function; girls; heart rate variability; human CREB1 protein; insight; male; neurodevelopment; neuromechanism; neuronal circuitry; programs; recombinase; research study; respiratory; tool; ward

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a dominant X-linked neurodevelopment disorder caused by mutation of Methyl- CpG-binding Protein 2 (MECP2). Affected patients have a variety of autonomic abnormalities that adversely affect quality of life for these individuals and likely contribute to the sub-population of RTT patients prone to sudden unexpected death. Male mice that completely lack MeCP2 function (Mecp2null/Y) reproduce many features of RTT including breathing abnormalities and constipation. Removing MeCP2 function from neural crest derivatives in the Wnt-1 expression domain reproduces the lethality observed in Mecp2null/Y mice. The hypothesis of this proposal is that dismption of MeCP2 function in the Wnt-1 domain causes autonomic dysfunction which ultimately leads to early death. To address the role of neural crest derived tissue in autonomic dysfunction during RTT pathogenesis, I plan the following experiments. I will perform detailed characterization of both the autonomic function in these animals as well as the cellular composition of the neural crest derivatives, with particular focus on the sympathetic ganglia. Additionally, I will use genetic techniques to introduce MeCP2 function in the neural crest of animals that otherwise lack MeCP2 function and determine if this is sufficient to restore normal lifespan and autonomic function. The research outlined in this proposal seeks to understand the causes of both the autonomic dysfunction as well as the early lethality observed in Mecp2null/Y mice. Ultimately, this understanding will help both develop therapeutic options for girls with RTT as well as provide insight into the neural mechanisms of autonomic control.

描述（由申请人提供）：Rett综合征（RTT）是由甲基CpG结合蛋白2（MECP 2）突变引起的显性X连锁神经发育障碍。受影响的患者具有各种自主神经异常，这些异常对这些个体的生活质量产生不利影响，并可能导致RTT患者亚群容易发生意外猝死。完全缺乏MeCP 2功能的雄性小鼠（Mecp 2null/Y）重现了RTT的许多特征，包括呼吸异常和便秘。从Wnt-1表达结构域的神经嵴衍生物中去除MeCP 2功能再现了在Mecp 2null/Y小鼠中观察到的致死性。该提议的假设是，Wnt-1结构域中MeCP 2功能的丧失导致自主神经功能障碍，其最终导致早期死亡。为了解决RTT发病过程中神经嵴衍生组织在自主神经功能障碍中的作用，我计划进行以下实验。我将对这些动物的自主神经功能以及神经嵴衍生物的细胞组成进行详细的表征，特别关注交感神经节。此外，我将使用遗传技术在缺乏MeCP 2功能的动物的神经嵴中引入MeCP 2功能，并确定这是否足以恢复正常的寿命和自主神经功能。该提案中概述的研究旨在了解自主神经功能障碍以及在Mecp 2null/Y小鼠中观察到的早期致死性的原因。最终，这种理解将有助于为RTT女孩制定治疗方案，并深入了解自主控制的神经机制。