Neurocardiac mechanisms of epilepsy with high risk of SUDEP

SUDEP高危癫痫的神经心脏机制

• 批准号: 10019197
• 负责人: Albert E Glasscock
• 金额: $ 22.87万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019197
• 关键词: Neurocardiac; mechanisms; epilepsy; risk; SUDEP

PROJECT SUMMARY/ABSTRACT Our long-term goal is to understand how gene mutations can cause epilepsy with cardiorespiratory comorbidities that contribute to risk of sudden unexpected death in epilepsy (SUDEP). People with epilepsy are 24 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. SUDEP is hypothesized to result from seizure-driven cardiorespiratory dysfunction that culminates in death. This proposal investigates the contribution of Kcna1 gene deletion to epilepsy, cardiac dysfunction, and SUDEP by using Cre recombinase-mediated conditional knockout models. Kcna1, a human epilepsy gene associated with SUDEP risk in patients, encodes predominantly-axonal Kv1.1 voltage-gated potassium channel α-subunits that are highly expressed in brain where they act to dampen neuronal excitability. Although the epilepsy phenotype of Kcna1-null mice has been studied extensively, the mechanisms and anatomical substrates responsible for their seizures, cardiac dysfunction and sudden death are poorly understood. In addition, new preliminary data reveals that Kcna1 is expressed in cardiomyocytes as well as brain; therefore, Kv1.1-deficiency in either organ could be sufficient to mediate cardiac arrhythmias and death. Utilizing a newly developed floxed Kcna1 mouse allele, the goal of this project is to test the hypotheses that brain region-specific Kv1.1-deficiency is sufficient to cause the epilepsy, cardiac phenotypes, and SUDEP observed in Kcna1-null mice and that the Kv1.1-deficient heart provides a permissive substrate for seizure- related cardiac abnormalities. Aim 1 examines neurocardiac effects of neuron-, corticolimbic-, and hindbrain- specific Kcna1 gene deletion. Aim 2 investigates cardiac dysfunction due to cardiac-specific Kcna1 gene deletion, as well as intrinsic dysfunction in denervated isolated hearts from global KOs. Aim 3 uses kainate- induced seizures in cardiac-specific cKOs to test whether Kv1.1-deficient hearts are inherently more prone to seizure-related functional and cardiac abnormalities. This research applies an innovative genetic approach to the study of brain-heart interactions in epilepsy by exploiting newly developed transgenic mouse models of SUDEP. These models allow us to identify previously unrecognized brain networks important for SUDEP pathophysiology and neurocardiac control, establishing them as candidate therapeutic targets for future studies. Furthermore, this study will improve our understanding of Kcna1 gene function and its role in human neurological and cardiac diseases.

项目概要/摘要 我们的长期目标是了解基因突变如何导致癫痫与心肺疾病 导致癫痫突然意外死亡 (SUDEP) 风险的合并症。 因不明病理原因突然死亡的可能性是普通人群的 24 倍； 死亡被归类为 SUDEP，是癫痫相关死亡的主要原因。 导致癫痫引起的心肺功能障碍，最终导致死亡。 使用 Cre 研究 Kcna1 基因缺失对癫痫、心功能障碍和 SUDEP 的影响 重组酶介导的条件敲除模型，Kcna1，一种与 SUDEP 相关的人类癫痫基因。 患者的风险，主要编码轴突 Kv1.1 电压门控钾通道 α 亚基， 尽管癫痫表型在大脑中高度表达，但它们的作用是抑制神经元的兴奋性。 Kcna1 缺失小鼠已被广泛研究，其机制和解剖基质 此外，新的初步数据对癫痫、心功能不全和猝死知之甚少。 揭示 Kcna1 在心肌细胞和大脑中表达；因此，任一器官中 Kv1.1 缺陷 可能足以介导心律失常和死亡。 该项目的目标是利用新开发的 floxed Kcna1 小鼠等位基因来检验假设 大脑区域特异性 Kv1.1 缺陷足以引起癫痫、心脏表型和 SUDEP 在 Kcna1 缺失小鼠中观察到，Kv1.1 缺陷的心脏为癫痫发作提供了允许的基质 目标 1 检查神经元、皮质边缘和后脑的神经心脏影响。 目标 2 研究心脏特异性 Kcna1 基因导致的心脏功能障碍。 缺失，以及来自全球 KO 的去神经离体心脏的内在功能障碍，Aim 3 使用红藻氨酸-。 在心脏特异性 cKO 中诱导癫痫发作，以测试 Kv1.1 缺陷的心脏是否本质上更容易发生 这项研究采用创新的遗传方法来治疗癫痫相关的功能和心脏异常。 利用新开发的转基因小鼠模型研究癫痫中的脑-心相互作用 SUDEP。这些模型使我们能够识别以前未被识别的对 SUDEP 很重要的大脑网络。 病理生理学和神经心脏控制，将其确立为未来的候选治疗靶点 此外，这项研究将增进我们对 Kcna1 基因功能及其在人类中的作用的理解。 神经系统和心脏病。