Neurocardiac mechanisms of epilepsy with high risk of SUDEP

SUDEP高危癫痫的神经心脏机制

基本信息

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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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