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

这项研究的长期目标是确定SUDEP风险生物标志物和脑-心-肺 介导SUDEP病理生理学的途径。癫痫患者的发病率是一般人的16倍 由于未知的病理原因而突然死亡;这些死亡被归类为SUDEP， 是癫痫相关死亡的主要原因。预测性SUDEP风险生物标志物仍然不存在， 所涉及的确切机制和途径知之甚少。克服这些障碍将使 准确的患者风险分层和监测，以及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 “器官间定向连接性分析”），以识别器官间定向相互作用的类型和性质。 脑（脑电图）、心脏（心电图）和肺（体积描记法）， 对SUDEP的易感性，并且可以用作SUDEP风险的可靠生物标志物， Aim 1中Kcna 1全基因敲除（KO）小鼠的检查。我们将测量这些动态变化 癫痫发作发生的时间和SUDEP的临近时间。Kcna 1 global KO小鼠，缺乏Kv1.1 通道，是SUDEP最具特征的遗传通道病模型之一， 在患者中观察到的SUDEP特征。在目标2中，我们将采用大脑和心脏特异性Kcna 1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、心脏和肺之间的定向连接的动力学损伤。在目标3中，我们将 研究了由于钠通道病引起的SUDEP的不同模型，Scn 8aN 1768 D小鼠，其携带 Nav1.6通道中的功能获得性突变，以确定是否有相同的异常脑-心-脑- 肺连通性可以在模型之间推广。 我们假设我们的分析将揭示大脑，心脏， 和肺与小鼠SUDEP易感性相关。这种脑心肺功能不全的模式 连接具有作为监测SUDEP风险的新的和更可靠的生物标志物的转化潜力， 癫痫患者的疾病进展，同时也揭示了潜在的病理生理机制。 在本提案中，对两种公认的SUDEP小鼠模型的脑-心-肺连接的评估将 为今后该生物工程技术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，可用于帮助预防策略。

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.