Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy

癫痫猝死的心脏机制

基本信息

  • 批准号:
    10454393
  • 负责人:
  • 金额:
    $ 70.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Sudden Unexpected Death in EPilepsy, or SUDEP, is a leading cause of death in patients with epilepsy. SUDEP mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and cardiac arrhythmias. We will take advantage of recent progress in the understanding of SUDEP risk in the genetic epilepsies to investigate the role of cardiac arrhythmias. SUDEP risk varies in a gene-specific manner. Loss-of- function variants in the voltage-gated sodium channel (VGSC) genes, SCN1A or SCN1B, are identified in patients with Dravet syndrome (DS) and gain-of-function variants in the VGSC SCN8A are found in patients with Early Infantile Epileptic Encephalopathy 13 (EIEE13). DS and EIEE13 patients have the highest SUDEP risk, up to 20%. In contrast, variants in chromodomain helicase DNA binding protein 2 (CHD2) are also associated with early onset EE, but SUDEP has not been reported in this population. SCN1A-, SCN1B-, SCN8A-, and CHD2- linked epilepsies are developmental and epileptic encephalopathies (DEEs), severe childhood epilepsies associated with cognitive and behavioral impairments. The familial focal epilepsies, are attributed to pathogenic variants in DEPDC5, encoding a member of the GATOR complex in the mTOR pathway. SUDEP is reported in 10% of these patients. Because VGSC genes are expressed in both heart and brain, we have proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in channelopathy-linked genetic epilepsies. Our overall goal is to understand the mechanisms of SUDEP in the genetic epilepsies. Our objectives are to use patient-derived or transgenic mouse cardiac myocytes (CMs) to understand how epileptic VGSC gene mutations alter CM function and arrhythmogenic potential, and to determine whether similar changes are found in non-ion channel epilepsy genes that are expressed in the heart. Our central hypothesis is that both ion channel and non- ion channel genetic epilepsies with high, but not low, SUDEP risk exhibit pro-arrhythmogenic changes in patient- derived CMs and mouse models. To ask whether abnormal CM excitability also occurs in a non-ion channel genetic epilepsy with high SUDEP risk, we will investigate DEPDC5 variant iPSC-CMs and Depdc5-/- mice. Finally, we will examine Chd2-/- mice and human iPSC-CMs with variants in CHD2, a non-ion channel gene with a low SUDEP risk, to test whether altered CM excitability is specific to genetic epilepsies with high SUDEP rates. Like the VGSCs, DEPDC5 and CHD2 are expressed in brain and heart. Our Specific Aims are: 1. To determine the effects of SCN1A, SCN1B, and SCN8A epilepsy variants on CM excitability using patient-derived iPSC-CMs. 2. To ascertain whether CMs from DEPDC5 patients or Depdc5+/- mice display abnormal excitability and whether Depdc5+/- mice have arrhythmia. 3. To determine whether CMs from CHD2 patients or Chd2+/- mice display abnormal excitability and whether Chd2+/- mice have arrhythmia. There are no effective therapies for any of the genetic epilepsies and no reliable biomarkers for SUDEP risk. This work may lead to the discovery of diagnostic biomarkers for SUDEP risk in the future.
癫痫猝死,或SUDEP,是癫痫患者死亡的主要原因。SUDEP 机制尚不清楚,尽管有证据表明呼吸暂停、自主神经功能障碍和 心律失常。我们将利用在理解遗传疾病中SUDEP风险方面的最新进展 以探讨癫痫对心律失常的作用。SUDEP的风险因基因而异。损失-- 电压门控钠通道(VGSC)基因的功能变体,SCN1A或SCN1B,在 DRAVET综合征(DS)和VGSC SCN8A功能获得变异的患者在 早期婴儿癫痫脑病13例(EIEE13)。DS和EIEE13患者的SUDEP风险最高, 降至20%。相反,染色域解旋酶DNA结合蛋白2(CHD2)的变异也与 早发性EE,但SUDEP在该人群中尚未报道。SCN1A-、SCN1B-、SCN8A-和CHD2- 相关癫痫是发育性和癫痫性脑病(DEE),严重的儿童癫痫 与认知和行为障碍有关。家族性局灶性癫痫,归因于 DEPDC5中的变体,编码mTOR途径中的鳄鱼复合体的一个成员。SUDEP的报告在 这些患者中有10%。由于VGSC基因在心脏和大脑中都有表达,我们提出 心律失常参与了通道病相关遗传性癫痫的SUDEP机制。我们的 总体目标是了解SUDEP在遗传性癫痫中的作用机制。我们的目标是使用 患者来源或转基因小鼠心肌细胞(CMS)了解癫痫VGSC基因突变 改变CM功能和致心律失常的电位,并确定是否在非离子中也发现了类似的变化 在心脏表达的经络癫痫基因。我们的中心假设是离子通道和非离子通道 离子通道遗传性癫痫的SUDEP风险高,但不低,患者表现出致心律失常的改变。 衍生的CMS和小鼠模型。询问非离子通道中是否也出现异常的CM兴奋性 遗传性癫痫具有高SUDEP风险,我们将研究DEPDC5变异的IPSC-CMS和Depdc5-/-小鼠。 最后,我们将研究CHD2-/-小鼠和人类IPSC-CMS中CHD2的变异,CHD2是一种非离子通道基因, 低SUDEP风险,以测试改变的CM兴奋性是否是具有高SUDEP发生率的遗传性癫痫特有的。 像VGSCs一样,DEPDC5和CHD2在大脑和心脏中表达。我们的具体目标是:1.确定 使用患者衍生的IPSC-CMS研究SCN1A、SCN1B和SCN8A癫痫变异对CM兴奋性的影响。 2.确定DEPDC5患者或Depdc5+/-小鼠的CMS是否表现出异常的兴奋性以及是否 Depdc5+/-小鼠有心律失常。3.确定CHD2患者或CHD2+/-小鼠的CMS是否显示 异常兴奋性和CHD2+/-小鼠是否存在心律失常。目前还没有有效的治疗方法来治疗任何一种 遗传性癫痫,没有可靠的SUDEP风险生物标志物。这项工作可能会导致发现诊断 未来SUDEP风险的生物标志物。

项目成果

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Lori L. Isom其他文献

I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain?
I. 钠通道 β 亚基的细胞和分子生物学:对疼痛的治疗意义?
Na+ channel subunits and Ig domains
钠离子通道亚单位和免疫球蛋白结构域
  • DOI:
    10.1038/383307b0
  • 发表时间:
    1996-09-26
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Lori L. Isom;William A. Catterall
  • 通讯作者:
    William A. Catterall
Modulation of Kv1 Voltage-Gated Potassium Channels by Sodium Channel Beta Subunits
  • DOI:
    10.1016/j.bpj.2011.11.3733
  • 发表时间:
    2012-01-31
  • 期刊:
  • 影响因子:
  • 作者:
    Hai M. Nguyen;Jeffrey D. Calhoun;Lori L. Isom;Alan L. Goldin;George K. Chandy
  • 通讯作者:
    George K. Chandy
Dramatic Improvement in Seizures With Phenytoin Treatment in an Individual With Refractory Epilepsy and a <em>SCN1B</em> Variant
  • DOI:
    10.1016/j.pediatrneurol.2020.03.012
  • 发表时间:
    2020-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    Louis T. Dang;Shane C. Quinonez;Bridget R. Becka;Lori L. Isom;Sucheta M. Joshi
  • 通讯作者:
    Sucheta M. Joshi
Ontology accelerates few-shot learning capability of large language model: A study in extraction of drug efficacy in a rare pediatric epilepsy
本体论加速大型语言模型的少样本学习能力:一项关于罕见儿童癫痫药物疗效提取的研究
  • DOI:
    10.1016/j.ijmedinf.2025.105942
  • 发表时间:
    2025-09-01
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Pedram Golnari;Katrina Prantzalos;Veronica Hood;Mary Anne Meskis;Lori L. Isom;Karen Wilcox;Jack M. Parent;Dennis Lal;Samden D. Lhatoo;Howard P. Goodkin;Elaine C. Wirrell;Kelly G. Knupp;Manisha Patel;Jeffrey A. Loeb;Joseph E. Sullivan;Lauren Harte-Hargrove;Brandy E. Fureman;Jeffrey Buchhalter;Satya S. Sahoo
  • 通讯作者:
    Satya S. Sahoo

Lori L. Isom的其他文献

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{{ truncateString('Lori L. Isom', 18)}}的其他基金

Development and Validation of a Transgenic Rabbit Model of Dravet Syndrome
Dravet 综合征转基因兔模型的开发和验证
  • 批准号:
    10574719
  • 财政年份:
    2023
  • 资助金额:
    $ 70.16万
  • 项目类别:
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
  • 批准号:
    10616678
  • 财政年份:
    2021
  • 资助金额:
    $ 70.16万
  • 项目类别:
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
  • 批准号:
    10397983
  • 财政年份:
    2021
  • 资助金额:
    $ 70.16万
  • 项目类别:
Epilepsy Multiplatform Variant Prediction (EpiMVP) - Admin Core
癫痫多平台变异预测 (EpiMVP) - 管理核心
  • 批准号:
    10670354
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Project-005
项目-005
  • 批准号:
    10455563
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Project-004
项目-004
  • 批准号:
    10455562
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Development of a Rabbit Model of SCN1A-linked Dravet Syndrome
SCN1A 相关 Dravet 综合征兔模型的开发
  • 批准号:
    10062010
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy
癫痫猝死的心脏机制
  • 批准号:
    10661021
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Project-005
项目-005
  • 批准号:
    10265447
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:
Project-005
项目-005
  • 批准号:
    10670389
  • 财政年份:
    2020
  • 资助金额:
    $ 70.16万
  • 项目类别:

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I-Corps:有效治疗阻塞性睡眠呼吸暂停中腭塌陷的神经刺激平台
  • 批准号:
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  • 批准号:
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    2024
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SBIR 第一阶段:无创闭环神经调节治疗阻塞性睡眠呼吸暂停
  • 批准号:
    2304265
  • 财政年份:
    2023
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Is gestational sleep apnea a previously unrecognized cause of maternal immune activation that predisposes male offspring to disease-relevant neural dysfunction?
妊娠期睡眠呼吸暂停是否是一种以前未被认识到的母体免疫激活的原因,导致男性后代容易出现与疾病相关的神经功能障碍?
  • 批准号:
    10680972
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    2023
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Upper airway collapsibility, loop gain and arousal threshold: an integrative therapeutic approach to obstructive sleep apnea
上气道塌陷、循环增益和唤醒阈值:阻塞性睡眠呼吸暂停的综合治疗方法
  • 批准号:
    10859275
  • 财政年份:
    2023
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The cardiovascular consequences of sleep apnea plus COPD (Overlap syndrome)
睡眠呼吸暂停加慢性阻塞性肺病(重叠综合征)对心血管的影响
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    10733384
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癫痫发作引起的呼吸暂停和 SUDEP 的神经回路
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开发治疗阻塞性睡眠呼吸暂停的 P4 医学方法
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    2023
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口腔功能筛查阻塞性睡眠呼吸暂停综合征及肌肉功能训练效果研究
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