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: 10453462
• 负责人: Craig Erickson
• 金额: $ 37.25万
• 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/10453462
• 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; Intellectual impairment; Knockout Mice; Link; Memantine; Methylation; Modeling; Mosaicism; Mus; Mutation; N-Methylaspartate; Nature; Neurobehavioral Manifestations; Outcome; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Placebo Control; 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; brain dysfunction; 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摘要 在过去 6 年里，我们脆性 X 综合症 (FXS) 研究联盟的人类研究部分 已确定与 FXS 中关键感觉、认知和症状相关的神经生理学改变。 我们首先报告了皮质过度兴奋，表现为静息时伽马能量过多和活动能力降低。 对听觉刺激产生适当的神经反应。我们证明了特征是并行保存的 小鼠脑电图实验（项目 2 团队）并在大脑皮层切片内的离体记录中进行了进一步探讨 Fmr1 KO 小鼠（项目 3 团队）。我们建立的合作即使不是最紧密的，也是其中之一 研究 FXS 的综合实验室到临床研究项目。我们的中心假设认为，缺乏 脆性 X 智力迟钝蛋白 (FMRP) 导致皮质过度兴奋，反映在升高的背景中 伽玛波段功率和改变的跨频调节过程。项目 1 的总体目标是 使用新范式更好地阐明神经生理学改变的本质及其临床意义 和分析技术，将发现从感觉皮层扩展到关联皮层，启动认知和分析的脑电图研究 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谷氨酸能和 GABA 能药物，并通过大样本研究与以下相关的神经生理学改变的异质性 遗传和人口特征。我们的目标是利用 FXS 对成人进行网络神经生理学建模， 通常发育和发育迟缓的对照受试者相匹配。在这项工作中，我们将评估 FXS 改变的认知过程中的神经生理学。我们将另外开发集成 对休息期间、感觉处理期间和认知活动期间的神经振荡变化进行建模。 我们的目标是在成人中进行新型安慰剂对照、单剂量、交叉机制药物挑战研究 与 FXS 一起。该药物挑战将重点关注 GABAB 神经传递的小分子靶向（阿巴氯芬）， GABAA 神经传递（BAER-101；以前的 AZD7325）和 NMDA 谷氨酸神经传递 （美金刚）。我们将并行评估药物对神经生理学结果、行为和认知的影响 在项目 2 中，在 Fmr1 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 通过根据性别评估 FXS 人类的神经生理学、认知和临床特征， 镶嵌状态和血液 FMRP 水平。我们还将评估神经生理学方面与年龄相关的变异性， 对 FXS 患者和青年健康对照者进行横断面研究的认知和临床特征 年龄范围。这些努力建立在我们迄今为止推进 FXS 转化医学努力的经验之上： 确保与我们的临床前合作者的实验紧密联系。这确保了临床前的结果 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，以建立 新的治疗靶点和新的生物标志物可加速 FXS 药物的发现。