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）：雷特综合征（RTT）是一种几乎只影响女性的神经系统疾病，由编码甲基 CpG 结合蛋白 2（MeCP2）的 X 连锁基因 MECP2 突变引起。患有 RTT 的婴儿在 6-18 个月大之前会经历表面上正常的发育，但随后会出现退化，失去习得的运动和语言技能，并在一生中逐渐发展出广泛的其他神经功能特征。大脑中实现和/或维持成熟的神经功能是否需要 MeCP2 功能一直不清楚，但最近的一项研究证明了成年裸鼠中 Mecp2 的重新表达如何能够挽救疾病特征，这使得证据的平衡转向了有利的方向MeCP2 的“维护”角色。然而，一个有趣的未解答的问题是，仅在产后早期神经发育的关键时期，MeCP2 的早期表达是否可能会改变随后蛋白质丢失后演变的疾病，这表明 MeCP2 在发育和神经成熟中的作用独立于其在维护中的作用。我假设 MeCP2 可能具有发育功能，并建议通过使用他莫昔芬诱导型 Cre/loxP 系统在成年小鼠中急性删除 Mecp2 来测试这一点。我预测，由于小鼠在出生后神经系统发育完成后将变得无效，因此小鼠将出现一种类似 RTT 的综合征，该综合征仅重现那些与需要 MeCP2 的维持功能相关的疾病特征，而无法重现与发育或成熟需求相关的特征MeCP2，从而提供关于 RTT 的两个假设的明确结论。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的 Mecp2 敲除后关键大脑区域的基因转录变化进行表征。初步数据证实了申请人设计的新型他莫昔芬给药方案对于成年（出生后第 60 天）小鼠 Mecp2 等位基因重组率达到 97% 的功效，并且行为试点研究揭示了成年诱导无效小鼠的明显行为变化。已完成的研究将探讨功能障碍的两个阶段是否会导致 RTT，以及产后发育期是否可以作为改善 RTT 患者预后的目标。此外，基因转录变化可能会优先针对候选遗传途径进行治疗。 公共卫生相关性：自闭症是一个主要的公共卫生问题，其病因可能有很多，目前尚不完全清楚，但雷特综合征 (RTT) 是一种具有自闭症许多特征的疾病，已知其病因是突变几乎每次都在基因 MECP2 中。在本研究中，这些知识将用于研究小鼠的 RTT，让我们深入了解自闭症的神秘机制，这有望让我们更多地了解 RTT 和自闭症等相关疾病是如何发生的以及如何改善这些患者”通过新疗法生活。