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iPSC and Mouse Neurocardiac Models (NS090364)

Specific Aims and Tasks

This core aims to determine whether heart rhythm disturbances are a cause of Sudden Unexplained Death in Epilepsy (SUDEP) in Dravet Syndrome, a severe childhood epilepsy with a high risk of SUDEP. The proposed studies involve a unique combination of experiments using patient-derived heart cells and neurons, mouse models, and patient electrocardiogram data obtained before, during and after seizures. Progress in these Aims will complement and synergize with the other projects in this proposal to not only uncover SUDEP mechanisms in Dravet Syndrome that will likely be applicable to other severe epilepsies, but also to provide advances in identifying biomarkers to define at-risk patients. Utilize iPSC-derived cardiac myocytes and autonomic neurons as well as mouse models to determine whether heart rhythm disturbances are a cause of SUDEP in Dravet Syndrome, a severe childhood epilepsy with a high risk of SUDEP
  • Focus on SCN1A and SCN1B mutations and investigation of their effect on cardiac and autonomic neuron excitability

Principal Investigators

Publication Links

  • Liu Y, Lopez-Santiago LF, Yuan Y, Jones JM, Zhang H, O’Malley HA, Patino GA, O’Brien JE, Rusconi R, Gupta A, Thompson RC, Natowicz MR, Meisler MH, Isom LL, Parent JM. Dravet Syndrome patient-derived neurons suggest a novel epilepsy mechanism. PMID 23821540.
  • Epi4K and EPGP Investigators. De novo mutations in the classic epileptic encephalopathies. PMID 23934111.
  • Auerbach DS, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL. Altered cardiac electrophysiology and SUDEP in a model of Dravet Syndrome. PMID 24155976.
  • Frampton JP, Shi H, Kao A, Parent JM, Takayama S. Delivery of proteases in aqueous two-phase systems enables direct purification of stem cell colonies from feeder cell co-cultures for differentiation into functional cardiomyocytes. PMID 23592706.
  • Villa-Diaz LG, Brown SE, Liu Y, Ross A, Lahann J, Parent JM, Krebsbach PH. Derivation of mesenchymal stem cells from human induced pluripotent stem cells cultured on synthetic substrates. PMID 22415987.
  • Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. Dentate granule cell neurogenesis is induced by seizures and contributes to aberrant network plasticity in the adult hippocampus. PMID 9133393 .
  • Parent JM, Valentin VV, Lowenstein DH. Prolonged seizures increase neurogenesis in the rostral forebrain subventricular zone-olfactory bulb pathway of the adult rat. PMID 9133393.
  • Wang TW, Zhang H, Parent JM. Retinoic acid regulates postnatal neurogenesis in the murine subventricular zone-olfactory bulb pathway. Development 132:2721-2732, 2005. PMID 15901659 .
  • Wang TW, Stromberg GP, Whitney JT, Brower NW, Klymkowsky MW, Parent JM. Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones. PMID 16680766.
  • Gong C, Wong TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. PMID 17314278
  • Kron MM, Zhang H, Parent JM. The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. PMID 20147533.
  • Singer BH, Gamelli AE, Fuller CL, Temme SJ, Parent JM*, Murphy GG*. Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young adult mice. PMCID 3069161.
  • Yasuda M, Johnson-Venkatesh EM, Zhang H, Parent JM, Sutton MA, Umemori H. Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. PMID 21689599.
  • Teixeira CM*, Kron MM*, Masachs N, Zhang H, Lagace DC, Martinez A, Reillo I, Duan X, Bosch C, Pujadas L, Brunso L, Song H, Eisch AJ, Borrell V, Howell BW, Parent JM#, Soriano E#. Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus. PMID 22933789.
  • Brackenbury, WJ, Yuan Y, O’Malley H, Parent JM, Isom LL. Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b null mice and precedes hyperexcitability. PMID 23277545.