Neurocardiac mechanisms of epilepsy with high risk of SUDEP

SUDEP高危癫痫的神经心脏机制

• 批准号: 9898482
• 负责人: Albert E Glasscock
• 金额: $ 32.38万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898482
• 关键词: Alleles; Anatomy; Arrhythmia; Atropine; Axon; Bradycardia; Brain; Brain Stem; Brain region; Cardiac; Cardiac Death; Cardiac Myocytes; Cessation of life; Data; Electrocardiogram; Electroencephalography; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epilepsy; Exhibits; Functional disorder; Future; Gene Deletion; Gene Expression; Gene Mutation; General Population; Genes; Goals; Heart; Heart Abnormalities; Heart Diseases; Human; Ion Channel; Kainic Acid; Knockout Mice; Link; Longevity; LoxP-flanked allele; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Mutation; Myocardial dysfunction; Neurons; Organ; Pathologic; Patients; Pattern; Phenotype; Research; Risk; Role; Seizures; Stress; Structure; Sudden Death; Suggestion; Survival Analysis; Technology; Testing; Time; Tissues; Transgenic Mice; Voltage-Gated Potassium Channel; Work; comorbidity; conditional knockout; gene function; genetic approach; high risk; hindbrain; improved; in vivo; innovation; kainate; knockout gene; mortality; mouse model; nervous system disorder; neural circuit; neuronal excitability; premature; sudden unexpected death in epilepsy; therapeutic candidate; therapeutic target

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.

项目总结/摘要 我们的长期目标是了解基因突变如何导致癫痫伴心肺功能障碍。 导致癫痫猝死（SUDEP）风险的合并症。癫痫患者 由于未知的病理原因突然死亡的可能性是普通人群的24倍;这些 死亡被归类为SUDEP，并代表癫痫相关死亡的主要原因。SUDEP是 假设是由心脏驱动的心肺功能障碍导致的，最终导致死亡。这项建议 通过使用Cre研究Kcna 1基因缺失对癫痫、心功能不全和SUDEP的贡献。 重组酶介导的条件敲除模型。Kcna 1基因与SUDEP相关 患者的风险，编码主要轴突Kv1.1电压门控钾通道α亚基， 它们在大脑中高度表达，在那里它们起到抑制神经元兴奋性的作用。虽然癫痫的表型 kcna 1基因敲除小鼠已被广泛研究，其机制和解剖学底物负责， 癫痫发作、心脏功能障碍和猝死的情况知之甚少。此外，新的初步数据 揭示Kcna 1在心肌细胞和大脑中表达;因此，Kv1.1缺乏症在任何器官中都是可能的。 足以导致心律失常和死亡 利用新开发的floxed Kcna 1小鼠等位基因，本项目的目标是测试假设 大脑区域特异性Kv1.1缺陷足以导致癫痫、心脏表型和SUDEP 在Kcna 1基因敲除小鼠中观察到，Kv1.1基因敲除小鼠的心脏为癫痫发作提供了一个允许的底物， 相关的心脏异常。目的1检查神经元，皮质边缘和后脑的神经心脏效应， 特异性Kcna 1基因缺失。目的2研究心脏特异性Kcna 1基因引起的心功能不全 缺失，以及内在的功能障碍，在去神经离体心脏从全球科斯。目标3使用红藻氨酸盐- 在心脏特异性cKO中诱导癫痫发作，以测试Kv1.1缺陷的心脏是否天生更容易发生 心脏相关的功能和心脏异常。这项研究采用了一种创新的遗传方法， 利用新开发的转基因小鼠模型研究癫痫的脑-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 问题研究此外，本研究将进一步加深我们对Kcna 1基因功能及其在人类中的作用的理解， 神经和心脏疾病。

项目成果

Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic-like behaviors due to Scn2a haploinsufficiency.

• DOI: 10.1002/brb3.2041
• 发表时间: 2021-04
• 期刊: Brain and behavior
• 影响因子: 3.1
• 作者: Indumathy J;Pruitt A;Gautier NM;Crane K;Glasscock E
• 通讯作者: Glasscock E

Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice.

• DOI: 10.3791/62735
• 发表时间: 2021-07-05
• 期刊: Journal of visualized experiments : JoVE
• 作者: Kumar P;Si M;Paulhus K;Glasscock E
• 通讯作者: Glasscock E

Directed Connectivity Analysis of the Neuro-Cardio- and Respiratory Systems Reveals Novel Biomarkers of Susceptibility to SUDEP.

• DOI: 10.1109/ojemb.2020.3036544
• 发表时间: 2020
• 期刊: IEEE open journal of engineering in medicine and biology
• 影响因子: 5.8
• 作者: Hutson TN;Rezaei F;Gautier NM;Indumathy J;Glasscock E;Iasemidis L
• 通讯作者: Iasemidis L

Kv1.1 subunits localize to cardiorespiratory brain networks in mice where their absence induces astrogliosis and microgliosis.

• DOI: 10.1016/j.mcn.2021.103615
• 发表时间: 2021-06
• 期刊: MOLECULAR AND CELLULAR NEUROSCIENCE
• 影响因子: 3.5
• 作者: Dhaibar, Hemangini A.;Hamilton, Kathryn A.;Glasscock, Edward
• 通讯作者: Glasscock, Edward

Neuron-specific Kv1.1 deficiency is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation.

神经元特异性 Kv1.1 缺陷足以导致癫痫、过早死亡和心肺失调。

• DOI: 10.1016/j.nbd.2020.104759
• 发表时间: 2020
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Trosclair,Krystle;Dhaibar,HemanginiA;Gautier,NicoleM;Mishra,Vikas;Glasscock,Edward
• 通讯作者: Glasscock,Edward