Neurobehavioral and biochemical outcome measures in Rett syndrome rodent models

雷特综合征啮齿动物模型的神经行为和生化结果测量

• 批准号: 9980446
• 负责人: Jeffrey L Neul
• 金额: $ 56.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980446
• 关键词: Address; Age; Alleles; Animal Model; Animals; Behavior; Biochemical; Biological Markers; Caring; Chronic; Clinical; Clinical Research; Communities; Data; Development; Disease; Disease Marker; Disease Progression; Educational workshop; Electroencephalography; Experimental Designs; Female; Future; Gait; Genes; Genetic; Genetic Transcription; Genotype; Goals; Human; Hybrids; Individual; Intellectual functioning disability; Intervention; Life; Link; Methyl-CpG-Binding Protein 2; Modeling; Mus; Neurodevelopmental Disorder; Onset of illness; Outcome; Outcome Measure; Participant; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Prediction of Response to Therapy; Prevalence; Public Health; Rattus; Reporting; Research; Respiration; Rett Syndrome; Rodent; Rodent Model; Sampling; Series; Severities; Severity of illness; Testing; Therapeutic Intervention; Therapeutic Uses; Translating; United States National Institutes of Health; Work; behavioral outcome; clinically relevant; disease-causing mutation; effective therapy; fluvastatin; genetic strain; girls; improved; life time cost; loss of function mutation; mouse model; neurobehavioral; novel strategies; postnatal; potential biomarker; pre-clinical; pre-clinical research; preclinical study; preclinical trial; sex; symptomatic improvement; therapy development; tool

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.

RETT综合征（RTT）是一种毁灭性的X连锁神经发育障碍，是主要原因之一 女孩的智力残疾和发展回归。 RTT是由功能丧失突变引起的 编码转录调节剂甲基-CPG结合蛋白2（MECP2）和几只小鼠的基因 通过针对同源的有针对性的破坏创建了概括疾病特征的模型 小鼠基因，MECP2。然而，至关重要的是开发RTT的疗法，但是，最好的做法是 进行临床前试验的标准 - 这对于确定和验证疗法至关重要 将要进行人类试验 - 尚未确定。为了满足这一需求，我们提出了研究 在精心挑选的RTT啮齿动物模型中，考虑了性别，遗传应变背景，物种和 自然疾病过程中的年龄。通过定义转化相关的发作和进展 神经行为表型和同时存在的血浆代谢物改变，我们将桥接行为 带有RTT潜在生物标志物的结果。此外，我们将使用遗传和药物策略来 检查生物标志物如何随着疾病改善而变化，以进一步对可能预测的标记进行分类 治疗反应。最后，为了优化结果的临床相关性，我们将测试已确定的代谢物 来自我们在RTT个体中的动物研究。我们的目标是确定表型和生化改变 在动物模型中可以作为临床前研究的结果指标的MECP2啮齿动物和最终 人类的临床研究。我们假设与疾病同时发生的血浆代谢产物异常 发作，随着疾病的进展而显着改变，并反之将 改进将是最有用的生物标志物，具有最高的转换性。具体 该提案的目的是i）定义和验证翻译相关的表型和同时发生的变化 在MECP2啮齿动物中的血浆代谢物中，ii）检查行为和代谢物谱的改变 在疾病改善期间，iii）评估MECP2啮齿动物生化改变的预测有效性 在RTT中。拟议的工作的独特功能应最大化其效用到RTT研究社区 并在RTT模型中加速临床前研究。综上所述，这些研究将提供必不可少的 努力从啮齿动物模型中确定具有最高可能性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 该领域必须采取强调对新方法的需求，或者促进最有效的 使用现有啮齿动物模型的临床前研究实践。