Neurobehavioral and biochemical outcome measures in Rett syndrome rodent models

Rett综合征（RTT）是一种毁灭性的X连锁神经发育障碍，是导致 智力残疾和发育退化的风险。RTT是由以下基因的功能缺失突变引起的： 编码转录调节剂甲基-CpG-结合蛋白2（MeCP 2）的基因和几种小鼠 已经通过靶向破坏同源基因来创建概括疾病特征的模型， 小鼠基因Mecp 2。目前迫切需要开发RTT的治疗方法，然而，最佳实践和 进行临床前试验的标准-这对于优先考虑和验证治疗至关重要， 是否会进行人体试验还没有确定。为了满足这一需求，我们建议开展研究， 在精心选择的RTT啮齿动物模型中，考虑了性别、遗传菌株背景、物种和 在疾病的自然过程中。通过定义预防性相关的 神经行为表型和共存的血浆代谢物改变，我们将架起行为桥梁 RTT的潜在生物标志物的结果。此外，我们将使用遗传和药理学策略， 检查生物标志物如何随着疾病的改善而变化，以进一步分类可能预测 治疗反应。最后，为了优化我们的结果的临床相关性，我们将测试鉴定的代谢物， 从我们的RTT个体动物研究中。我们的目标是确定表型和生化改变， Mecp 2啮齿类动物可作为动物模型临床前研究的结果指标， 人类的临床研究。我们假设，与疾病同时发生的血浆代谢物异常 发病时，随着疾病进展而显著改变，相反，随着疾病进展而正常化。 改进将作为具有最高可翻译性程度的最有用的生物标志物。具体 该提案的目的是i）定义和验证预防相关的表型和共同发生的变化 Mecp 2啮齿类动物血浆代谢物中，ii）检查行为和代谢物谱的改变 iii）评估Mecp 2啮齿动物生化改变的预测有效性 在RTT中。拟议工作的独特功能应最大限度地发挥其效用，RTT研究界 并加速RTT模型的临床前研究。总之，这些研究将提供不可或缺的 为努力从啮齿动物模型中识别出最有可能发生 转化为有效的人类疗法。无论结果如何，结果将确定方向， 外地必须采取的行动，要么强调需要新的办法，要么促进最有效的办法， 使用现有啮齿动物模型的临床前研究实践。

Rett syndrome (RTT) is a devastating X-linked neurodevelopmental disorder and one of the leading causes of intellectual disability and developmental regression in girls. RTT is caused by loss-of-function mutations in the gene encoding the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) and several mouse models that recapitulate features of the disease have been created by targeted disruption of the homologous mouse gene, Mecp2. There is a crucial need to develop therapies for RTT, however, the best practices and standards for performing preclinical trials – which will be essential for prioritizing and validating therapies that are to be advanced to human trials – have not yet been determined. To address this need, we propose studies in well-chosen RTT rodent models that consider factors such as sex, genetic strain background, species, and age during the natural course of disease. By defining the onset and progression of translationally-relevant neurobehavioral phenotypes and co-occurring plasma metabolite alterations, we will bridge behavioral outcome with potential biomarkers for RTT. In addition, we will use genetic and pharmacological strategies to examine how biomarkers may change with disease improvement to further classify markers that may predict treatment response. Finally, to optimize the clinical relevance of our results, we will test metabolites identified from our animal studies in RTT individuals. Our goal is to identify the phenotypic and biochemical alterations in Mecp2 rodents that can serve as outcome measures in preclinical studies in animal models and eventual clinical studies in humans. We hypothesize that abnormalities in plasma metabolites that co-occur with disease onset, become markedly altered with disease progression and conversely normalized with disease improvement will serve as the most useful biomarkers with the highest degree of translatability. The Specific Aims of the proposal are i) to define and validate translationally-relevant phenotypes and co-occurring changes in plasma metabolites among Mecp2 rodents, ii) to examine alterations in behavior and metabolite profile during disease improvement, and iii) to evaluate the predictive validity of Mecp2 rodent biochemical alterations in RTT. The unique features of the proposed work should maximize its utility to the RTT research community and accelerate preclinical studies in RTT models. Taken together, these studies will provide the indispensable ground-work for endeavors to identify from rodent models the interventions that have the highest likelihood of translating into effective human therapies. Regardless of the outcome, the results will define the direction that the field must take, either underscoring the need for new approaches, or promoting the most effective preclinical research practices using existing rodent models.