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Cardiac Gene and Circuit Mechanisms (NS090340)

Specific Aims and Tasks

The primary goal of this project is to contribute to our understanding of the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological spreading network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.

Principal Investigator

Core Personnel

Eric Raap

Core Administrator

Ryan Seo

Laboratory Manager

Isamu Aiba, Ph.D.

Post Doctoral Associate

Cory Massey, Ph.D.

Post Doctoral Associate


Xander Wehrens, M.D., Ph.D.


Publication Links

  • Summary of the 2016 Partners Against Mortality in Epilepsy (PAME) Conference. Epilepsy Curr. 2016 Nov-Dec;16(Suppl 1):1-17. PMID 28070172.
  • Lopez AY, Wang X, Xu M, Maheshwari A, Curry D, Lam S, Adesina AM, Noebels JL, Sun QQ, Cooper EC. Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Mol Psychiatry. 2016 Dec 13. PMID 27956739 .
  • Aiba I, Wehrens XH, Noebels JL. Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proceedings of the National Academy of Sciiences U S A. 2016 Aug 16;113(33). PMID 27482086.
  • Hernandez CC, Klassen TL, Jackson LG, Gurba K, Hu N, Noebels JL, Macdonald RL. Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population. PLoS One. 2016 Sep 13;11(9). PMID 27622563.
  • Noebels J. Hippocampal abnormalities and sudden childhood death. Forensic Sci Med Pathol. 2016 Jun;12(2):198-9. PMID 27094436.
  • Aiba I, Noebels JL. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med. 2015 Apr 8;7(282):282ra46. PMID 25855492.
  • Bernard C. Spreading depression: epilepsy’s wave of death. Sci Transl Med. 2015 Apr 8;7(282):282fs14. PMID 25855491.
  • Glasscock E, Voigt N, McCauley MD, Sun Q, Li N, Chiang DY, Zhou XB, Molina CE, Thomas D, Schmidt C, Skapura DG, Noebels JL, Dobrev D, Wehrens XH. Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation. Basic Res Cardiol. 2015 Sep;110(5):505. PMID 26162324.
  • Lhatoo, S., J. Noebels, V. Whittemore, and The NINDS Center for SUDEP Research. Sudden Unexpected Death in Epilepsy (SUDEP): Identifying Risk and Preventing Mortality. Epilepsia 56(11):1700-6, 2015. PMID 26494436.
  • Noebels J. Pathway-driven discovery of epilepsy genes. Nature Neuroscience. 2015 Mar;18(3):344-50. PMID 25710836.
  • Noebels JL. Single-Gene Determinants of Epilepsy Comorbidity. Cold Spring Harbor Perspective in Medicine. 2015 Nov 2;5(11). PMID 26525453.
  • Klassen TL, Bomben VC, Patel A, et al. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 2014 Feb;55(2):e6-12. PMID 24372310.
  • Qi Y, Wang J, Bomben VC, Li DP, Chen SR, Sun H, Xi Y, Reed JG, Cheng J, Pan HL, Noebels JL, Yeh ET. Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron. 2014 Sep 3;83(5):1159-71. PMID 25189211.
  • Cole AJ, Eskandar E, Mela T, Noebels JL, Gonzalez RG, McGuone D. N Engl J Med. 2013 368:2304Case records of the Massachusetts General Hospital. Case 18-2013: a 32-year-old woman with recurrent episodes of altered consciousness. New England Journal of Medicine 2013 Jun 13;368(24):2304-12. PMID 23758236.
  • Holth JK, Bomben VC, Reed JG, Inoue T, Youngkin L, Youngkin SG, Pautler RG, Botas J, Noebels, JL. Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy. Journal of Neuroscience 2013 Jan 23;33(4):1651-9. PMID 23345237.
  • Glasscock E, Qian J, Kole MJ, Noebels JL. Transcompartmental reversal of single fiber hyperexcitability in juxtaparanodal Kv1.1 –deficient vagus nerve axons by activation of nodal KCNQ channels. Journal of Physiology 2012, Aug 15;590(16):3913-26. PMID 22641786.
  • Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 2011 Jun 24;145(7):1036-48. PMID 21703448.
  • Glasscock, E, Yoo J, Chen TT, Klassen TL, Noebels JL Kv1.1 Potassium Channel Deficiency Reveals Brain-Driven Cardiac Dysfunction as a Candidate Mechanism for Sudden Unexplained Death in Epilepsy. Journal of Neuroscience 2010 Apr 14;30(15):5167-75. PMID 20392939.
  • Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia of Heart and Brain: KCNQ1 mutations link epilepsy and sudden death. Science Translational Medicine 2009, 1:98-106. PMID 20368164.
  • Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia of Heart and Brain: KCNQ1 mutations link epilepsy and sudden death. Science Translational Medicine 2009, 1:98-106. PMID 20368164.
  • Glasscock E, Qian J, Yoo JW, Noebels JL. Masking Epilepsy by Combining Two Epilepsy Genes.Nature Neuroscience 2007, Dec;10(12):1554-8. PMID 17982453.
  • Lopez-Santiago LF, Meadows LS, Ernst SJ, Chen C, Malhotra JD, McEwen DP, Speelman A, Noebels JL, Maier SK, Lopatin AN, Isom LL. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. Journal of Molecular and Cellular Cardiology 2007 Nov;43(5):636-47. PMID 17884088.
  • Chen C, Westenbroek RE, Xu X, Edwards CA, Sorenson DR, Chen Y, McEwen DP, O'Malley H, Bharucha V, Meadows LS, Knudsen GA, Vilaythong A, Noebels JL, Saunders TL, Scheuer T, Shrager P, Catterall WA, Isom LL. Mice Lacking Sodium Channel 1 Subunits Display Defects in Neuronal Excitability, Sodium Channel Expression, and Nodal Architecture. Journal of Neuroscience 2004 Apr 21;24(16):4030-42. PMID 15102918.
  • Hartman HA, Colom LV, Sutherland ML, Noebels JL. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nature Neuroscience 1999 Jul;2(7):593-5. PMID 10404176.