Network Mechanisms, Biomarkers and Pharmacology of Fragile X Syndrome in Humans

人类脆性 X 综合征的网络机制、生物标志物和药理学

• 批准号: 10271298
• 负责人: Craig Erickson
• 金额: $ 37.64万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271298
• 关键词: Acute; Adult; Age; Auditory; Award; Behavior; Behavioral; Biological Markers; Blood; Brain; Childhood; Clinical; Clinical Markers; Clinical Trials; Cognition; Cognitive; Collaborations; Coupling; Cross-Sectional Studies; Developmental Delay Disorders; Disease model; Dose; Double-Blind Method; Electroencephalography; Electrophysiology (science); Ensure; FMR1; Female; Fragile X Syndrome; Frequencies; Genetic; Glutamate Receptor; Glutamates; Heterogeneity; Human; Impairment; Individual; Knockout Mice; Link; Memantine; Methylation; Modeling; Mosaicism; Mus; Mutation; N-Methylaspartate; Nature; Neurobehavioral Manifestations; Outcome; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Process; Regulation; Reporting; Research; Rest; Sampling; Sensory; Severities; Slice; Speed; Symptoms; System; Techniques; Testing; Translating; Translational Research; Translations; Validation; Work; Youth; advanced analytics; age related; analytical method; association cortex; auditory stimulus; base; behavioral impairment; behavioral phenotyping; behavioral study; bench to bedside; clinically significant; cognitive process; connectome; disease heterogeneity; drug development; drug discovery; drug response prediction; experience; experimental study; follow-up; gamma-Aminobutyric Acid; graph theory; habituation; improved; male; molecular marker; mouse model; network models; neural model; neuronal circuitry; neuronal excitability; neurophysiology; neurotransmission; new therapeutic target; novel; novel marker; patient variability; personalized care; pre-clinical; precision medicine; programs; protein expression; relating to nervous system; response; sex; small molecule; somatosensory; synergism; targeted biomarker; translational medicine

Project 1 Abstract Over the past 6 years, the human research component of our Fragile X Syndrome (FXS) Research Consortium has established neurophysiological alterations linked to key sensory, cognitive, and symptom correlates in FXS. We first reported cortical hyperexcitability in the form of excessive gamma power at rest and a reduced ability to mount appropriate neural responses to auditory stimuli. We demonstrated that features are conserved in parallel murine EEG experiments (Project 2 team) and probed further in ex vivo recordings within cortical slices in the Fmr1 KO mouse (Project 3 team). Our established collaborations represent one of, if not the most tightly integrated bench to bedside research programs studying FXS. Our central hypothesis posits that the absence of fragile X mental retardation protein (FMRP) results in cortical hyperexcitability reflected in elevated background gamma band power and altered cross-frequency regulatory processes. The overarching aims of Project 1 are to better clarify the nature of neurophysiological alterations and their clinical implications using new paradigms and analytic techniques, extend findings from sensory to association cortex, initiate EEG studies of cognitive and behavioral processes, use our neurophysiological biomarkers to predict and track response to glutamatergic and GABAergic drugs, and with large samples investigate heterogeneity in neurophysiological alterations related to genetic and demographic features. We aim to pursue network neurophysiology modeling in adults with FXS, typically developing and developmentally delayed matched control subjects. In this work we will evaluate neurophysiology during cognitive processes that are altered in FXS. We will additionally develop integrated modeling of neural oscillatory alterations across rest, during sensory processing and during cognitive activity. We aim to conduct novel placebo-controlled, single-dose, crossover mechanistic drug challenge studies in adults with FXS. This drug challenge will focus on small molecule targeting of GABAB neurotransmission (arbaclofen), GABAA neurotransmission (BAER-101; formerly AZD7325), and NMDA glutamatergic neurotransmission (memantine). We will evaluate drug impact on neurophysiology outcomes, behavior, and cognition in parallel with testing of the same drugs in the Fmr1 KO mouse in Project 2. Third, we aim to resolve heterogeneity within human FXS by evaluating neurophysiological, cognitive, and clinical profiles in humans with FXS based on sex, mosaic status, and blood FMRP level. We will additionally evaluate age-related variability in neurophysiologic, cognitive, and clinical profiles in a cross-sectional study of patients with FXS and healthy controls in the youth age range. These efforts build on our experience to date moving forward FXS translational medicine efforts by ensuring tight linkages to the experiments of our preclinical collaborators. This ensures that results of preclinical work can be forward translated while in parallel our human findings can inform preclinical approaches to establish new therapeutic targets and novel biomarkers to speed drug discovery for FXS.

项目1 在过去的6年里，我们的脆性X综合征（FXS）研究联盟的人类研究部分 已经建立了与FXS中关键感觉、认知和症状相关的神经生理学改变。 我们首先报道了皮质过度兴奋，表现为休息时过度的伽马能量， 对听觉刺激做出适当的神经反应我们证明了特征是平行守恒的 小鼠EEG实验（项目2团队），并进一步探索在皮层切片内的离体记录， Fmr 1 KO小鼠（项目3团队）。我们建立的合作代表了一个，如果不是最紧密的 研究FXS的综合实验室到床边研究项目。我们的中心假设假定， 脆性X智力低下蛋白（FMRP）导致皮质过度兴奋，反映在升高的背景中 伽马波段功率和改变的交叉频率调节过程。项目1的总体目标是 为了更好地阐明神经生理学改变的性质及其临床意义， 和分析技术，将发现从感觉皮层扩展到联想皮层，启动认知和 行为过程，使用我们的神经生理学生物标志物来预测和跟踪对多巴胺能的反应， GABA能药物，并与大样本调查异质性神经生理学改变有关， 遗传和人口统计学特征。我们的目标是在患有FXS的成年人中进行网络神经生理学建模， 典型地发育中和发育延迟的匹配对照受试者。在这项工作中，我们将评估 FXS中认知过程中的神经生理学改变。此外，我们还将开发集成 在休息期间，感觉处理期间和认知活动期间的神经振荡变化的建模。 我们的目标是在成人中进行新的安慰剂对照、单次给药、交叉机制药物激发研究 关于FXS这项药物挑战将集中在GABAB神经传递的小分子靶向（arbaclofen）， GABAA神经传递（BAER-101;以前称为AZD 7325）和NMDA受体能神经传递 （美金刚）。我们将同时评估药物对神经生理学结果、行为和认知的影响 在项目2的Fmr 1 KO小鼠中测试相同的药物。第三，我们的目标是解决内部的异质性， 人类FXS通过基于性别评估患有FXS的人类的神经生理学、认知和临床特征， 嵌合状态和血液FMRP水平。我们还将评估年龄相关的神经生理变化， 在一项对FXS患者和年轻健康对照者的横断面研究中， 年龄范围。这些努力建立在我们迄今为止推进FXS转化医学工作的经验基础上， 确保与我们临床前合作者的实验紧密联系。这确保了临床前试验的结果 工作可以向前转化，同时我们的人类发现可以为临床前方法提供信息， 新的治疗靶点和新的生物标志物，以加速FXS的药物发现。