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Research Summary

奥尔巴赫实验室的长期目标是调查这种疾病的流行情况, risk factors, 以及大脑(癫痫)和心脏(心律失常)双重电干扰的机制. 我们特别感兴趣的是提高我们对导致癫痫患者突然意外死亡的多系统级联事件的理解。, which will hopefully identify markers for SUDEP.

Bedside-to-Bench-to-Bedside Approach: We take a multi-system (brain & heart) and multi-scale (molecular, biochemical, cellular, organ, in vivo, 以及临床研究脑和心脏电性疾病的方法. 我们进行患者数据库分析，以检查癫痫发作和心律失常的共同患病率和风险. 然后使用细胞和动物模型的疾病，我们执行分子/生化和电生理的方法来了解这些神经心脏病理的潜在机制. Ultimately, these results are validated using patient databases, and thus complete the full bedside-to-bench-to-bedside paradigm.

Bedside to Bench to Bedside Research Approach

Multi System Image
认识和治疗遗传性离子通道疾病的多系统方法:奥尔巴赫实验室的“从床到台到床”的研究方法涉及对有脑(癫痫/癫痫)和心脏(心律失常)电干扰史的人类进行临床研究。. 此外，我们还建立了遗传性心律失常疾病的遗传兔模型. 它使我们能够通过在分子上进行实验来探索这些异常的潜在原因, biochemical, cellular, and whole animal levels.  Each aspect of the research program feeds and motivates the others, creating a productive research cycle.
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Clinical Research Projects (Retrospective Datasets & Prospective Recordings from Wearable Sensors)

数以百万计的美国人患有癫痫，他们有很高的猝死风险.g., SUDEP.) Unfortunately, the underlying mechanisms remain unknown.

由于心脏事件是SUDEP的一个机制，我们从心脏开始. In genetic models of epilepsy, we showed it is critical to look outside the brain, 因为这些突变会导致心电功能的改变, which include altered ion channel activity, hyperexcitability, and arrhythmias.

Following a bench-to-bedside paradigm, 我们报道了严重遗传性癫痫患者的心电异常和近致死性心律失常的病例. 我们使用在心脏病学领域被广泛接受的分析工具, but new to epilepsy and SUDEP, 确定具有心脏相关性猝死风险的癫痫患者人群. Additionally, 我们使用可穿戴技术来获取连续的多系统记录, which enables us to capture events outside the hospital. 目标是开发一种全面的SUDEP风险评估工具，以帮助识别具有SUDEP风险的癫痫患者, so that measures can be put in place to prevent SUDEP from occurring.

SUDEP

Clinical Database Studies数据收集于患者基线间期和癫痫发作前后. Auerbach实验室在这段时间内研究患者的心电图，希望能识别出SUDEP风险的心脏生物标志物.

基础科学项目(长QT综合征的细胞和动物模型)

Percent of participants with seizures graph

Starting at the patient level, 我们证明了一种经典研究的遗传性心律失常疾病的患者, Long QT Syndrome (LQTS), are at an increased risk of seizures. Yet, the underlying cause for these seizures remains unknown. We developed a novel mutant rabbit model of LQTS, which reproduces the neuro-cardiac pathologies seen in LQTS patients. 它使我们能够进行转化研究，以调查LQTS中心律失常和癫痫发作的机制. Ongoing experimental approaches are at the molecular, biochemical, cellular electrophysiology, organ, and in vivo levels.

Long QT Syndrome我们发现遗传性心律失常患者有较高的癫痫发作/癫痫史, Long QT syndrome, compared to their genotype negative family members. 2型长QT综合征患者癫痫发作的发生率最高.

basic science image

Rabbit Model of Long QT Syndrome Type 2Auerbach实验室已经开发了多种突变兔系，可以模拟长QT综合征2型患者的神经心脏电异常. Video/EEG/ECG recordings, as well as respiratory measures, 是否从兔子身上记录以验证模型并检查潜在的机制.

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EEG/ECG Recordings of Rabbits: Using a clinical grade EEG acquisition device, Auerbach实验室同时记录多达7只兔子的连续EEG/ECG记录.

Publications

Recent Publications

*Corresponding Author, ₶First Author

  • Ryan JM₶, Wagner KT₶, Yerram S, Concannon C, Lin JX, Rooney P, Hanrahan B, Titoff V, Connolly N, Cranmer R, DeMaria N, Xia X, Mykins B, Erickson S, Couderc JP, Schifitto G, Hughes I, Wang D, Erba G, Auerbach DS*. 心率和自主神经生物标志物可区分惊厥癫痫vs. functional or dissociative seizures. Seizure: European Journal of Epilepsy, 2023, ISSN 1059-1311. doi: 10.1016/j.seizure.2023.08.015
  • Singh V₶, Ryan JM₶, Auerbach DS*, 对于癫痫猝死的统一假设还为时过早:还需要大量的研究来理解多系统级联. Epilepsia, 2023. doi: 10.1111/epi.17636
  • Sanchez-Conde FG, Jimenez-Vazquez EN, Auerbach DS*, Jones DK*. The ERG1 K+ Channel and Its Role in Neuronal Health and Disease. Frontiers in Molecular Neuroscience. 2022 May 3. doi: 3389/fnmol.2022.890368
  • Auerbach DS*, Muniz CF. [Editorial] Cardiac Safety of Lamotrigine: Still Awaiting a Verdict. Neurology. 2022 Mar 8, doi: 1212/WNL.0000000000200189
  • Toth J, Waickman A, Jost J, Seltzer L, Vinocur JM, Auerbach DS*. 在2q24缺失相关的发育性和癫痫性脑病中，近致死性室性心动过速的识别和成功处理. Seizure June 2021 doi: 1016/j.seizure.2021.06.003
  • Bosinski C, Wagner KT, Zhou, X., Liu, L., Auerbach DS*. Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.  Vis. Exp.2021 Mar 27;(169), doi: 10.3791/62256 PMID: 33843929.
  • French JA, Perucca E, Sander J, Bergfeldt L, Baulac M, Auerbach DS, Keezer M, Thijs R, Devinsky O, Vossler D, WeltyT. FDA关于拉莫三嗪对心脏影响的安全警告:来自特设ILAE/AES工作组的建议. Epilepsia Open 2021 Feb 25 doi: 1002/epi4.12475
  • French JA, Perucca E, Sander J, Bergfeldt L, Baulac M, Auerbach DS, Keezer M, Thijs R, Devinsky O, Vossler D, Welty T. FDA关于拉莫三嗪对心脏影响的安全警告:来自特设ILAE/AES工作组的建议. Epilepsy Currents 2021 March Vol 6 (1) 45-48 doi:1177/1535759721996344 PMID: 33641454.
  • Kim BS₶, Auerbach DS₶, Sadhra H, Ling FS, Godwin M, Mohan A, Yule DI, Wagner L, Rich DQ, Tura S, Morrell C, Goldenberg I, Cameron SJ. 心肌梗死后血小板蛋白酶激活受体信号的性别特异性转换. Arterioscler Thromb Vasc Biol. 2020 Nov 12 PMID: 33176447PMCID: PMC7770120.
  • DeMaria N, Selmi A, Kashtan S, Xia X, Wang M, Zareba W, Couderc JP, Auerbach DS*. Autonomic and Cardiac Repolarization Lability in Long QT Syndrome. Autonomic Neuroscience: Basic & Clinical. Epub 2020 Sep 6. PMID:32942226 PMCID: PMC7704776.
  • Tylock K, Auerbach DS, Tang ZZ, Thornton C, Dirksen RT. 心脏扩增cug重复RNA表达小鼠QRS-和qtc -间期延长的生物物理机制. J. Gen. Physiol. 2020 152 (2): e201912450, PMCID: PMC7062505. PMID: 31968060
  • Frasier CR, Zhang H, Offord J, Dang LT, Auerbach DS, Shi H, Chen C, Goldman AM, Eckhardt LL, Bezzerides VJ, Parent JM, Isom LL. 通道病变作为Dravet综合征患者源性心肌细胞的SUDEP生物标志物. Stem Cell Reports. 2018. Sep 11;11(3):626-634. doi: 10.1016/j.stemcr.2018.07.012. Epub 2018 Aug 23. PMID: 30146492; PMCID: PMC6135724. Epub 2018/08/28.
  • 王m, Szepietowska B, Polonsky B, McNitt S, Moss AJ, Zareba W, Auerbach DS. 长QT综合征患者抗抑郁治疗相关的心脏事件风险. Am J Cardiol. 2018 Jan 15;121(2):182-187. PubMed PMID: 29174490; PMCID: PMC5742310.
  • 李建军，李建军，李建军，李建军，李建军. 长QT综合征患者服用抗癫痫药物时心脏事件的风险. Transl Res. 2018 Jan;191:81-92.e7. PubMed PMID: 29121487; PMCID: PMC5733703.
  • Bao Y, Willis BC, Frasier CR, Lopez-Santiago LF, Lin X, Ramos-Mondragón R, Auerbach DS, Chen C, Wang Z, Anumonwo J, Valdivia HH, Delmar M, Jalife J, Isom LL. Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. Circ Arrhythm Electrophysiol. 2016 Dec;9(12)PubMed PMID: 27932425; PMCID: PMC5161227
  • Carrell ST, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, Thornton CA. Dmpk基因缺失或反义敲除不会损害小鼠的心脏或骨骼肌功能. Hum Mol Genet. 2016 Aug 13;PubMed PMID: 27522499. PMCID: PMC5291200
  • Auerbach DS*, McNitt S, Gross RA, Zareba W, Dirksen RT, Moss AJ. Genetic biomarkers for the risk of seizures in long QT syndrome. Neurology. 2016 Oct 18;87(16):1660-1668. PubMed PMID: 27466471; PMCID: PMC5085072.

Complete List of Published Work

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