Dissecting the Developmental and Epileptic Components of Encephalopathy in DEE

剖析 DEE 脑病的发育和癫痫成分

• 批准号: 10633843
• 负责人: Vaishnav Krishnan
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633843
• 关键词: Ablation; Adult; Affect; Age; Arousal; Behavior; Behavior Therapy; Behavioral; Biological Assay; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Calcium; Caregivers; Circadian Rhythms; Clinical Trials; Cognitive; Communication; Complex; Coupled; DNA Sequence Alteration; Deterioration; Development; Developmental Delay Disorders; Disease; Disease remission; Dissociation; Dopamine; Down-Regulation; Electroencephalography; Emotional; Encephalopathies; Epilepsy; Exhibits; Foundations; Frequencies; Functional disorder; Genes; Genetic; Genome; Growth; Hippocampus; Home; Human; Hyperactivity; Image; Impairment; In Situ; Intellectual functioning disability; Knockout Mice; Learning; Lesion; Life; Link; Measurement; Measures; Mediating; Mediator; Memory; Midbrain structure; Modeling; Molecular; Monitor; Motor; Mus; Mutant Strains Mice; Pathway interactions; Patient Care; Patients; Periodicity; Personal Satisfaction; Phenotype; Physiological; Play; Precision therapeutics; Process; Proteomics; Recurrence; Rest; Risk; Rodent; Role; Seizures; Shapes; Sleep; Sleeplessness; Spontaneous Remission; Symptoms; Syndrome; Tamoxifen; Telemetry; Testing; Therapeutic; Up-Regulation; Variant; Visualization; Voltage-Gated Potassium Channel; Work; anxious; behavior measurement; cognitive function; comorbidity; dentate gyrus; design; developmental genetics; digital; dopaminergic neuron; drug discovery; emotional functioning; epileptic encephalopathies; ergonomics; exome sequencing; experience; experimental study; feeding; genetic approach; improved; innovation; insight; instrument; instrumentation; motor deficit; mouse model; multimodality; mutant; neurobehavioral; neuropsychiatric disorder; neuropsychiatry; novel; pharmacologic; pre-clinical; response; sensory integration; social reciprocity; synergism; transcription factor; translational therapeutics; wireless

Project Summary/Abstract In patients with developmental and epileptic encephalopathies (DEEs), early life seizures and intellectual disability are frequently accompanied by disturbances in arousal/sleep, communication/social reciprocity, feeding and/or sensory integration. These neurobehavioral comorbidities are hypothesized to reflect a synergy of two independent but intertwined processes: (i) an inciting lesion (genetic or structural) capable of itself altering neurodevelopmental trajectories, and (ii) periods of frequent seizures, particularly early in life, that further exacerbate developmental delays. In many patients, behavioral deterioration may begin prior to seizure onset and may persist despite complete seizure control (or spontaneous remission). With whole exome sequencing, we now recognize a rapidly expanding list of genetic DEEs, which have lent to genetically informed mouse models that are critically poised to develop the urgently needed precision therapies that extend beyond seizure control. Today’s models are actively revealing novel mechanistic insights into molecular and circuit-level patho- physiology, thanks to the latest advances in genome manipulation and measurements of omics, functional connectivity and calcium imaging, as well as continued ergonomic improvements in rodent electro- encephalography. In contrast, there have been few technical and conceptual innovations within preclinical assays for neurobehavioral impairment, leaving the field reliant on behavioral batteries that may be confounded by primary disturbances in sleep/arousal, seizure recency, motor deficits and human olfactory interference. In this application, we apply the latest advances in homecage instrumentation and automated videotracking to define endpoints for DEE-related neurobehavioral impairment that are derived under experimenter-free conditions (remote behavioral telemetry). We describe a mouse model of DEE with early life seizures that displays a robust multifaceted behavioral syndrome with core features of hyperactivity and insomnia. Using this model system, this proposal tests the central hypothesis of genetic DEE, that the neurobehavioral consequences of the causative genetic lesion can be dissociated from the behavioral aftereffects of recurrent early life seizures. In Aim 1, we examine a transcription factor that is activated by seizures in the hippocampus, and which is known to shape a range of emotional and cognitive behaviors. In Aim 2, we test the importance of early life seizures by comparing behavioral and epileptic consequences of an early versus late genetic ablation. In Aim 3, we connect hyperactivity and insomnia in our mutant mice to primary disruptions in 5h ultradian rhythms of activity, and test whether pharmacological or behavioral interventions to restore ultradian rhythms exert therapeutic benefits. In the short term, these experiments will build molecular and circuit-level insights while delivering a set of novel neurobehavioral endpoints to facilitate drug discovery in DEE models. In the long term, this work develops the preclinical foundation for digital neuropsychiatry, where subjective measures of behavioral wellbeing are supplemented with continuous, in situ wearable-derived endpoints that inform clinical trials and patient care.

项目摘要/摘要 在发育和癫痫性脑病（DEES）的患者中，早期癫痫发作和肠胃 残疾经常伴随着唤醒/睡眠，沟通/社会互惠的干扰， 喂养和/或感觉整合。假设这些神经行为合并症以反映协同作用 在两个独立但交织在一起的过程中：（i）一种能够改变的刺激性病变（遗传或结构） 神经发育轨迹以及（ii）经常癫痫发作的时期，尤其是生命的早期，进一步 加剧发展延迟。在许多患者中，行为延迟可能会在癫痫发作之前开始 并且可能会持续目的地完全癫痫发作控制（或赞助商缓解）。随着整个外显子组测序， 现在，我们认识到一个迅速扩展的遗传蠕虫列表，这些清单借出了遗传知情的鼠标 严重中毒以开发出急需的精确疗法的模型，这些疗法超出了癫痫发作 控制。当今的模型正在积极揭示对分子和电路级病情的新机械见解。 生理学，感谢您在基因组操纵和OMICS，功能性的测量方面的最新进展 连通性和钙成像，以及啮齿动物电 - 持续的人体工程学改进 脑电图。相反，临床前几乎没有技术和概念创新 神经行为障碍的测定法，使场地依赖于可能混淆的行为电池 通过睡眠/唤醒的主要干扰，癫痫发作，运动定义和人类嗅觉干扰。在 在此应用 定义与DEE相关的神经行为障碍的终点 条件（远程行为遥测）。我们描述了一种用早期癫痫发作的迪伊的老鼠模型 显示出强大的多方面行为综合征，具有多动症和失眠的核心特征。使用此 模型系统，该建议检验了遗传DEE的中心假设，即神经行为后果 病因病变可以与复发的早期生命癫痫发作的行为解脱。 在AIM 1中，我们检查了一种转录因子，该转录因子被海马中的癫痫发作激活，并已知 塑造各种情感和认知行为。在AIM 2中，我们测试了早期癫痫发作的重要性 比较早期与晚期遗传消融的行为和癫痫后果。在AIM 3中，我们连接 我们突变小鼠对5H超级节奏的主要干扰的多动症和失眠，并测试 无论是药理还是行为干预措施以恢复超级节奏具有治疗益处。在 短期，这些实验将建立分子和电路级别的见解，同时提供一组新颖 神经行为终点，以促进DEE模型中的药物发现。从长远来看，这项工作发展了 数字神经精神病学的临床前基础，行为健康的主观度量是 补充了连续的原位可穿戴式终点，这些终点为临床试验和患者护理提供了信息。