Investigating the homeostatic role of MeCP2 in mature brain

研究 MeCP2 在成熟大脑中的稳态作用

• 批准号: 8060117
• 负责人: Christopher McGraw
• 金额: $ 3.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-11 至 2013-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060117
• 关键词: Address; Adult; Affect; Age-Months; Alleles; Autistic Disorder; Behavioral; Brain; Brain region; Data; Development; Disease; Dose; Educational process of instructing; Equilibrium; Excision; Female; Functional disorder; Genes; Genetic; Genetic Recombination; Hypothalamic structure; Infant; Knock-out; Knockout Mice; Knowledge; Language; Life; Link; Maintenance; Mediating; Methyl-CpG-Binding Protein 2; Mus; Mutation; Nervous System Physiology; Neuraxis; Neurologic; Outcome; Pathway interactions; Patients; Phase; Phenotype; Physiological; Pilot Projects; Proteins; Public Health; Regimen; Rett Syndrome; Role; Syndrome; System; Tamoxifen; Testing; Time; Tissues; behavior test; critical period; experience; improved; interest; motor learning; nervous system disorder; novel; postnatal; skills

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a neurological disorder almost exclusively affecting females and caused by mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2 (MeCP2). Infants with RTT experience ostensibly normal development until 6-18 months of age but then regress, losing learned motor and language skills and progressively developing a broad range of additional neurological features over the course of their life. Whether MeCP2 function is required either to achieve and/or to maintain mature neurological function in the brain has remained historically unclear, but a recent study demonstrating how reexpression of Mecp2 in adult null mice can rescue features of disease has shifted the balance of evidence in favor of a "maintenance" role for MeCP2. An interesting unanswered question, however, is whether early expression of MeCP2 only through the critical period of early post-natal neurological development might alter the disease that evolves following later loss of the protein, suggesting a role for MeCP2 in development and neurological maturation that is independent of its role in maintenance. I hypothesize that there likely are developmental functions of MeCP2 and propose to test this by acutely deleting Mecp2 in adult mice using the tamoxifen inducible Cre/loxP system. I predict that since mice will become null after post-natal neurological development has been completed, mice will develop a RTT-like syndrome that recapitulates only those disease features related to maintenance functions that require MeCP2 while failing to recapitulate features related to developmental or maturational requirements of MeCP2, thus providing definitive conclusions about the two hypotheses of RTT. Mice will be characterized for general and behavioral phenotypes (using a battery of established mouse physiological and behavioral tests), neuropathological changes in the central nervous system, and gene transcriptional changes in a key brain region following adult induced knockout of Mecp2. Preliminary data confirms the efficacy of a novel tamoxifen dosing regimen devised by the applicant for 97% recombination of the Mecp2 allele in adult (post natal day 60) mice and behavioral pilot studies reveal distinct behavioral changes in adult induced null mice. The completed studies will address whether two phases of dysfunction contribute to RTT and whether post-natal developmental periods might be targeted to improve the outcomes of RTT patients. Furthermore, gene transcriptional changes may prioritize targeting of candidate genetic pathways for therapy. PUBLIC HEALTH RELEVANCE: The causes of autism - a major public health concern - are likely many and are not totally clear at this time, but the cause of Rett syndrome (RTT), a disease with many features of autism, is known to be mutations in the gene MECP2 almost every time. In the present study, this knowledge will be employed to study RTT in mice, giving us an inroad into the enigmatic mechanisms of autism, which is expected to teach us more about both how RTT and related disorders like autism occur and how to improve these patients' lives through new therapy.

描述（由申请人提供）：Rett综合征（RTT）是一种神经系统疾病，几乎只影响女性，由X连锁基因MECP 2突变引起，MECP 2编码甲基-CpG结合蛋白2（MeCP 2）。患有RTT的婴儿在6-18个月之前表面上发育正常，但随后会退化，失去学习的运动和语言技能，并在其生命过程中逐渐发展出广泛的其他神经功能。MeCP 2功能是否需要实现和/或维持大脑中的成熟神经功能在历史上仍然不清楚，但最近的一项研究表明，成年裸小鼠中Mecp 2的再表达如何挽救疾病的特征，已经改变了证据的平衡，有利于MeCP 2的“维持”作用。然而，一个有趣的未回答的问题是，MeCP 2的早期表达是否仅通过出生后早期神经发育的关键时期可能会改变后来蛋白质丢失后演变的疾病，这表明MeCP 2在发育和神经成熟中的作用独立于其在维持中的作用。我假设MeCP 2可能具有发育功能，并建议通过使用他莫昔芬诱导的Cre/loXP系统急性删除成年小鼠中的Mecp 2来测试这一点。我预测，由于小鼠出生后神经系统发育完成后将变为无效，小鼠将发展出RTT样综合征，该综合征仅概括与需要MeCP 2的维持功能相关的疾病特征，而无法概括与MeCP 2的发育或成熟要求相关的特征，从而提供关于RTT的两个假设的明确结论。将对小鼠的一般和行为表型（使用一系列已建立的小鼠生理和行为测试）、中枢神经系统的神经病理学变化以及成年诱导Mecp 2敲除后关键脑区的基因转录变化进行表征。初步数据证实了由申请人设计的新的他莫昔芬给药方案对于成年（纳塔尔后第60天）小鼠中Mecp 2等位基因的97%重组的功效，并且行为初步研究揭示了成年诱导的无效小鼠中的明显行为变化。已完成的研究将解决两个阶段的功能障碍是否有助于RTT，以及出生后发育期是否可以改善RTT患者的结局。此外，基因转录变化可以优先靶向候选遗传途径进行治疗。 公共卫生关系：自闭症的原因-一个主要的公共卫生问题-可能有很多，目前还不完全清楚，但Rett综合征（RTT）的原因，一种具有自闭症许多特征的疾病，几乎每次都被认为是基因MECP 2的突变。在本研究中，这些知识将用于研究小鼠的RTT，使我们能够深入了解自闭症的神秘机制，这有望教会我们更多关于RTT和自闭症等相关疾病如何发生以及如何通过新疗法改善这些患者的生活。