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，也是主要原因之一 关于女孩智力残疾和发育退化的问题。RTT是由基因的功能缺失突变引起的 转录调节因子甲基-CpG结合蛋白2(MeCP2)的编码基因和几只小鼠 重述疾病特征的模型是通过有针对性地破坏同源基因而创建的 小鼠基因MeCP2。迫切需要开发RTT的治疗方法，然而，最佳做法和 执行临床前试验的标准-这将是优先和验证以下疗法的关键 是否会被推进到人体试验--还没有确定。为了满足这一需求，我们提出了研究 在精心选择的RTT啮齿动物模型中，考虑了性别、遗传品系背景、物种和 自然病程中的年龄。通过定义与翻译相关的 神经行为表型和共同发生的血浆代谢物改变，我们将桥接行为 RTT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来 检查生物标记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，为了优化我们结果的临床相关性，我们将测试已确定的代谢物。 来自我们对RTT个体的动物研究。我们的目标是确定表型和生化变化 在动物模型的临床前研究中可以作为结果衡量的MeCP2啮齿动物 在人类身上的临床研究。我们假设与疾病同时发生的血浆代谢物异常 发病，随着疾病的进展而明显改变，反之随着疾病的发展而正常化 改进将成为最有用的生物标志物，具有最高的可译性。具体的 该提案的目的是：i)定义和验证与翻译相关的表型和共现的变化 在MeCP2啮齿动物的血浆代谢物中，II)检查行为和代谢物的变化 在疾病改善期间，以及iii)评估MeCP2啮齿动物生化变化的预测有效性 在RTT中。拟议工作的独特特点应最大限度地提高其对RTT研究界的效用 并加快RTT模型的临床前研究。总而言之，这些研究将提供不可或缺的 努力从啮齿动物模型中确定最有可能出现的干预措施的基础工作 转化为有效的人类疗法。无论结果如何，结果都将定义 实地必须采取行动，要么强调需要新的办法，要么促进最有效的 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.