Biomarkers of SUDEP risk based on brain-heart-lungs network dynamics

基于脑-心-肺网络动力学的SUDEP风险生物标志物

• 批准号: 10561946
• 负责人: Albert E Glasscock
• 金额: $ 65.05万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561946
• 关键词: Affect; Afferent Pathways; Animal Model; Autonomic nervous system; Benchmarking; Biological; Biological Markers; Biomedical Engineering; Brain; Cardiac; Cessation of life; Classification; Development; Disease Progression; Efferent Pathways; Electrocardiogram; Electroencephalography; Epilepsy; Evaluation; Exhibits; Foundations; Frequencies; Functional disorder; Future; General Population; Genetic; Goals; Heart; Impairment; Intervention; Knock-out; Knockout Mice; Light; Lung; Measurement; Measures; Mediating; Methods; Modeling; Monitor; Mus; Myocardial dysfunction; National Institute of Neurological Disorders and Stroke; Nature; Neurons; Organ; Pathologic; Pathway interactions; Patient risk; Patients; Pattern; Persons; Pharmacology; Phenobarbital; Play; Plethysmography; Potassium; Predisposition; Prevention; Prevention strategy; Publishing; Research; Risk; Risk Assessment; Role; SCN8A gene; Seizures; Sodium; System; Techniques; Testing; Time; Ventilatory Depression; Work; brain abnormalities; brain dysfunction; candidate identification; candidate marker; clinical application; conditional knockout; gain of function mutation; insight; knockout animal; knockout gene; mortality; mouse model; multidisciplinary; novel marker; pharmacologic; predictive marker; respiratory; risk prediction; risk stratification; sudden unexpected death in epilepsy; translational potential

The long-term goal of this research is to identify SUDEP risk biomarkers and the brain-heart-lungs pathways mediating SUDEP pathophysiology. People with epilepsy are 16 times more likely than the general population to die suddenly for unknown pathological reasons; these deaths are classified as SUDEP and represent the leading cause of epilepsy-related mortality. Predictive SUDEP risk biomarkers still do not exist and the exact mechanisms and pathways involved are poorly understood. Overcoming these barriers would enable accurate patient risk stratification and monitoring, and the development of effective preventive strategies. In this work, we propose to employ a new multidisciplinary bioengineering systems approach (termed “inter-organ directed connectivity analysis”) to identify the type and nature of directional interactions between the brain (electroencephalography), heart (electrocardiography), and lungs (plethysmography) that underlie susceptibility to SUDEP and that could be utilized as reliable biomarkers of SUDEP risk, beginning with examination of Kcna1 global knockout (KO) mice in Aim 1. We will measure how these dynamics change over time when seizures occur and as the time to SUDEP approaches. Kcna1 global KO mice, which lack Kv1.1 channels, are one of the best characterized genetic channelopathy models of SUDEP, exhibiting essential features of SUDEP observed in patients. In Aim 2, we will employ brain- and heart-specific Kcna1 conditional KO (cKO) models and pharmacology to begin to identify the underlying biological basis of the observed impairment of dynamics in the directional connectivities between brain, heart and lungs. In Aim 3, we will then examine a different model of SUDEP due to sodium channelopathy, the Scn8aN1768D mouse, which carries a gain-of-function mutation in Nav1.6 channels, to determine whether the same patterns of abnormal brain-heart- lung connectivity can be generalized across models. We hypothesize that our analyses will reveal pathological functional interactions between the brain, heart, and lungs that are associated with SUDEP susceptibility in mice. Such patterns of faulty brain-heart-lung connectivity have translational potential as new and more reliable biomarkers for monitoring SUDEP risk and disease progression in epilepsy patients, while also shedding light on potential pathophysiological mechanisms. Evaluation of brain-heart-lungs connectivity across two accepted mouse models of SUDEP in this proposal will lay the foundation for future clinical application of this bioengineering technique in epilepsy patients with the hope of providing individualized SUDEP risk assessment that can be used to aid preventative strategies.

这项研究的长期目标是确定SUDEP风险生物标记物和脑-心-肺 介导SUDEP病理生理学的通路。癫痫患者的患病几率是普通人群的16倍。 人口因未知的病理原因突然死亡；这些死亡被归类为SUDEP和 是癫痫相关死亡的主要原因。可预测的SUDEP风险生物标记物仍然不存在 其中涉及的确切机制和途径还知之甚少。克服这些障碍将使 准确的患者风险分层和监测，并制定有效的预防策略。 在这项工作中，我们建议采用一种新的多学科生物工程系统方法(称为 “器官间定向连通性分析”)，以确定各器官之间定向相互作用的类型和性质 脑(脑电)、心脏(心电)和肺(体积描记) 对SUDEP的易感性，这可以作为SUDEP风险的可靠生物标记物，从 在AIM 1中对KcNA1全局基因敲除(KO)小鼠的检查。我们将测量这些动力学如何改变 癫痫发作发生的时间和SUDEP时间的临近。Kcna1全球KO小鼠，缺乏Kv1.1 经络，是SUDEP最具特征性的遗传性经络病模型之一，表现出 观察患者的SUDEP特点。在目标2中，我们将使用大脑和心脏特定的KcNA1条件 KO(CKO)模型和药理学开始确定观察到的潜在生物学基础 大脑、心脏和肺之间定向连接的动力学障碍。在《目标3》中，我们将 检查另一种由钠通道病引起的SUDEP模型，Scn8aN1768D小鼠，它携带一种 Nav1.6通道中的功能获得突变，以确定是否相同模式的异常大脑-心脏- 肺连接可以在不同的模型中推广。 我们假设我们的分析将揭示大脑、心脏和大脑之间的病理性功能相互作用， 和肺与小鼠的SUDEP易感性有关。脑心肺病的这种模式 连接性作为新的、更可靠的生物标志物具有翻译潜力，用于监测SUDEP风险和 在癫痫患者的疾病进展，同时也揭示了潜在的病理生理机制。 在这项提案中，对两种被接受的SUDEP小鼠模型的脑-心-肺连接性进行评估将 为这项生物工程技术未来在癫痫患者中的临床应用奠定基础 提供个性化的SUDEP风险评估，以帮助制定预防策略。