Circadian analysis of peripheral and brain samples in epilepsy patients

癫痫患者外周血和脑样本的昼夜节律分析

• 批准号: 10440732
• 负责人: Taylor John Abel
• 金额: $ 22.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440732
• 关键词: Adolescent and Young Adult; Adverse event; Amygdaloid structure; Attention; Autopsy; Behavioral; Biological Markers; Blood; Blood specimen; Brain; Brain Diseases; Brain region; Cessation of life; Chronotherapy; Circadian Rhythms; Clinic; Clinical; Cognition; Corpus striatum structure; Data; Development; Disease; Environmental Risk Factor; Epilepsy; Evaluation; Event; Excision; Female Adolescents; Future; Gene Expression; Genes; Health; Hippocampus (Brain); Hour; Human; Individual; Lead; Male Adolescents; Measures; Metabolic; Molecular; Myocardial Infarction; Neurologic; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Pathology; Patients; Pattern; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Pilot Projects; Predictive Factor; Process; Proxy; Publishing; Research Personnel; Resected; Resistance; Sampling; Schedule; Seizures; Sleep; Stroke; Therapeutic; Time; Tissues; Transcript; Urine; aged; brain tissue; circadian; cognitive testing; cohort; differential expression; experience; insight; machine learning algorithm; metabolomics; neocortical; novel; personalized approach; prediction algorithm; predictive marker; prevent; putamen; sex; side effect; statistical and machine learning; suprachiasmatic nucleus; transcriptome sequencing; treatment response

PROJECT SUMMARY Nearly every process that occurs in the brain and the body follows a 24 hour cycle. Moreover, adverse health events such as heart attacks, stroke and seizures tend to occur at particular times of day. Seizures often follow a rhythmic pattern, but this pattern can be very different from patient to patient. If one can determine the circadian factors that predict that a seizure is likely to occur, then this allows proper timing of treatments to provide the most therapeutic impact with fewest side effects. Indeed, several groups are starting to apply this chronotherapy as a personalized approach to predict and treat a number of disorders including seizures. While sleep/wake activity measures are a gross predictor of the optimal time of day for medication, they are confounded by a variety of environmental factors and do not always align with endogenous rhythms. The use of peripheral markers in blood or urine could serve to fine tune chronotherapeutic approaches as they are easily obtained in the clinic. Indeed, researchers have now been able to accurately predict the phase of the master clock in the suprachiasmatic nucleus (SCN) using as little as 1-2 blood samples. Moreover, better understanding of phase relationships between peripheral markers, SCN phase, and molecular rhythms in parts of the brain that experience seizures, would help not only in the administration of chronotherapy, but also in our understanding of why the brain might experience a seizure at a particular time of day. In this study, we have the rare opportunity to obtain human brain tissue, blood, and urine samples at the same time of day from male and female adolescents and young adults (~25 subjects) undergoing surgical resection for the treatment of seizures. In addition, prior to surgery, we will collect sleep/wake data, behavioral data, cognitive assessments, assessments of seizure patterns and psychiatric evaluations. This will allow us for the first time to measure transcripts and metabolites with known rhythms across multiple peripheral and brain samples at the same time of day from the same individuals, giving us precise data regarding how markers of phase in the peripheral samples align with markers in brain regions in which seizures occur. We will also be able to determine how these molecular and metabolic measures align with sleep/wake measures and various clinical features, seizure patterns, and differences between healthy and disease tissue, paying particular attention to any sex and developmental differences. This data will inform future mechanistic studies of why seizures occur at particular times of day, and optimize the use of peripheral samples to serve as biomarkers for the most appropriate timing for treatment.

项目概要 大脑和身体中发生的几乎每个过程都遵循 24 小时循环。而且，对健康不利 心脏病发作、中风和癫痫发作等事件往往发生在一天中的特定时间。癫痫发作通常会随之而来 有节奏的模式，但这种模式因患者而异。如果能确定昼夜节律 预测癫痫可能发生的因素，然后这允许适当的治疗时机以提供 最大的治疗效果和最少的副作用。事实上，一些团体已经开始应用这种时间疗法 作为预测和治疗包括癫痫发作在内的多种疾病的个性化方法。睡觉/醒来时 活动测量是一天中最佳用药时间的粗略预测，它们受到以下因素的影响： 环境因素多种多样，并不总是与内源性节律一致。外围标记的使用 血液或尿液中的检测可以用于微调时间治疗方法，因为它们很容易在诊所获得。 事实上，研究人员现在已经能够准确预测主时钟的相位。 只需 1-2 个血液样本即可检测视交叉上核 (SCN)。此外，更好地理解相位 外周标记、SCN 相位和大脑部分分子节律之间的关系 经历癫痫发作，不仅有助于时间疗法的实施，而且有助于我们的理解 为什么大脑可能会在一天中的特定时间经历癫痫发作。在这项研究中，我们有难得的机会 在一天中的同一时间从男性和女性身上获取人类脑组织、血液和尿液样本 接受手术切除以治疗癫痫发作的青少年和年轻人（约 25 名受试者）。在 此外，在手术前，我们将收集睡眠/觉醒数据、行为数据、认知评估、评估 癫痫发作模式和精神病学评估。这将使我们能够第一次测量成绩单并 在一天中的同一时间从多个外周和大脑样本中提取具有已知节律的代谢物 相同的个体，为我们提供了关于外围样本中的相位标记如何与 发生癫痫发作的大脑区域的标记。我们还将能够确定这些分子和 代谢测量与睡眠/觉醒测量以及各种临床特征、癫痫模式和 健康组织和患病组织之间的差异，特别注意任何性别和发育 差异。这些数据将为未来的机制研究提供信息，以了解为什么癫痫发作在一天中的特定时间发生，以及 优化外周样本的使用，作为最合适治疗时机的生物标志物。