請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54610
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
dc.contributor.author | Ming-Shian Tsai | en |
dc.contributor.author | 蔡明憲 | zh_TW |
dc.date.accessioned | 2021-06-16T03:07:38Z | - |
dc.date.available | 2020-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-06-24 | |
dc.identifier.citation | Amaral DG, Scharfman HE, Lavenex P (2007) The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Progress in brain research 163: 3-22
Andrade DM, Hamani C, Lozano AM, Wennberg RA (2010) Dravet syndrome and deep brain stimulation: seizure control after 10 years of treatment. Epilepsia 51: 1314-1316 Arakawa M, Shiozuka M, Nakayama Y, Hara T, Hamada M, Kondo S, Ikeda D, Takahashi Y, Sawa R, Nonomura Y, Sheykholeslami K, Kondo K, Kaga K, Kitamura T, Suzuki-Miyagoe Y, Takeda S, Matsuda R (2003) Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice. Journal of biochemistry 134: 751-758 Aras LM, Isla J, Mingorance-Le Meur A (2015) The European patient with Dravet syndrome: Results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome. Epilepsy behavior : E B 44C: 104-109 Auerbach DS, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL (2013) Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PloS one 8: e77843 Auvin S, Lecointe C, Dupuis N, Desnous B, Lebon S, Gressens P, Dournaud P (2013) Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature rat brain. Epilepsia 54: 2082-2090 Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL (1999) Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. The Journal of clinical investigation 104: 375-381 Bender AC, Natola H, Ndong C, Holmes GL, Scott RC, Lenck-Santini PP (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiology of disease 54: 297-307 Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51: 676-685 Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, Walker LC (2006) Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain research 1075: 68-80 Bidou L, Allamand V, Rousset JP, Namy O (2012) Sense from nonsense: therapies for premature stop codon diseases. Trends in molecular medicine 18: 679-688 Bozzi Y, Casarosa S, Caleo M (2012) Epilepsy as a neurodevelopmental disorder. Frontiers in psychiatry 3: 19 Brachet A, Leterrier C, Irondelle M, Fache MP, Racine V, Sibarita JB, Choquet D, Dargent B (2010) Ankyrin G restricts ion channel diffusion at the axonal initial segment before the establishment of the diffusion barrier. The Journal of cell biology 191: 383-395 Brauchi S, Orta G, Salazar M, Rosenmann E, Latorre R (2006) A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 26: 4835-4840 Brendel C, Belakhov V, Werner H, Wegener E, Gartner J, Nudelman I, Baasov T, Huppke P (2011) Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model. Journal of molecular medicine 89: 389-398 Brunklaus A, Zuberi SM (2014) Dravet syndrome--from epileptic encephalopathy to channelopathy. Epilepsia 55: 979-984 Burgess DL, Noebels JL (2000) Calcium channel defects in models of inherited generalized epilepsy. Epilepsia 41: 1074-1075 Butt SJ, Fuccillo M, Nery S, Noctor S, Kriegstein A, Corbin JG, Fishell G (2005) The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48: 591-604 Cao D, Ohtani H, Ogiwara I, Ohtani S, Takahashi Y, Yamakawa K, Inoue Y (2012) Efficacy of stiripentol in hyperthermia-induced seizures in a mouse model of Dravet syndrome. Epilepsia 53: 1140-1145 Caraballo RH (2011) Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic diet. Epilepsia 52 Suppl 2: 79-82 Carpenter DO, Alving BO (1968) A contribution of an electrogenic Na+ pump to membrane potential in Aplysia neurons. The Journal of general physiology 52: 1-21 Catterall WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26: 13-25 Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. The Journal of neuroscience : the official journal of the Society for Neuroscience 28: 11768-11777 Ceulemans B, Boel M, Claes L, Dom L, Willekens H, Thiry P, Lagae L (2004) Severe myoclonic epilepsy in infancy: toward an optimal treatment. Journal of child neurology 19: 516-521 Chabardes S, Kahane P, Minotti L, Koudsie A, Hirsch E, Benabid AL (2002) Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic disorders : international epilepsy journal with videotape 4 Suppl 3: S83-93 Cheah CS, Westenbroek RE, Roden WH, Kalume F, Oakley JC, Jansen LA, Catterall WA (2013) Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels 7: 468-472 Cheah CS, Yu FH, Westenbroek RE, Kalume FK, Oakley JC, Potter GB, Rubenstein JL, Catterall WA (2012) Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proceedings of the National Academy of Sciences of the United States of America 109: 14646-14651 Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW (2012) Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation. Human molecular genetics 21: 4270-4285 Chiron C, Dulac O (2011) The pharmacologic treatment of Dravet syndrome. Epilepsia 52 Suppl 2: 72-75 Claes LR, Deprez L, Suls A, Baets J, Smets K, Van Dyck T, Deconinck T, Jordanova A, De Jonghe P (2009) The SCN1A variant database: a novel research and diagnostic tool. Human mutation 30: E904-920 Copley RR (2004) Evolutionary convergence of alternative splicing in ion channels. Trends in genetics : TIG 20: 171-176 Coppola G, Capovilla G, Montagnini A, Romeo A, Spano M, Tortorella G, Veggiotti P, Viri M, Pascotto A (2002) Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy research 49: 45-48 Crow JF (2006) Age and sex effects on human mutation rates: an old problem with new complexities. Journal of radiation research 47 Suppl B: B75-82 Dalic L, Mullen SA, Roulet Perez E, Scheffer I (2015) Lamotrigine can be beneficial in patients with Dravet syndrome. Developmental medicine and child neurology 57: 200-202 de Felipe P, Luke GA, Brown JD, Ryan MD (2010) Inhibition of 2A-mediated 'cleavage' of certain artificial polyproteins bearing N-terminal signal sequences. Biotechnology journal 5: 213-223 de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD (1989) Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain research 495: 387-395 Deller T, Martinez A, Nitsch R, Frotscher M (1996) A novel entorhinal projection to the rat dentate gyrus: direct innervation of proximal dendrites and cell bodies of granule cells and GABAergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 16: 3322-3333 Depienne C, Bouteiller D, Keren B, Cheuret E, Poirier K, Trouillard O, Benyahia B, Quelin C, Carpentier W, Julia S, Afenjar A, Gautier A, Rivier F, Meyer S, Berquin P, Helias M, Py I, Rivera S, Bahi-Buisson N, Gourfinkel-An I, Cazeneuve C, Ruberg M, Brice A, Nabbout R, Leguern E (2009a) Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS genetics 5: e1000381 Depienne C, Trouillard O, Saint-Martin C, Gourfinkel-An I, Bouteiller D, Carpentier W, Keren B, Abert B, Gautier A, Baulac S, Arzimanoglou A, Cazeneuve C, Nabbout R, LeGuern E (2009b) Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. Journal of medical genetics 46: 183-191 Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55: 791-802 Dickerson LW, Bonthius DJ, Schutte BC, Yang B, Barna TJ, Bailey MC, Nehrke K, Williamson RA, Lamb FS (2002) Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC-3 voltage-gated chloride channels. Brain research 958: 227-250 Donnelly ML, Luke G, Mehrotra A, Li X, Hughes LE, Gani D, Ryan MD (2001) Analysis of the aphthovirus 2A/2B polyprotein 'cleavage' mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal 'skip'. The Journal of general virology 82: 1013-1025 Dressler A, Trimmel-Schwahofer P, Reithofer E, Muhlebner A, Groppel G, Reiter-Fink E, Benninger F, Grassl R, Feucht M (2015) Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. Epilepsy research 109: 81-89 Du L, Damoiseaux R, Nahas S, Gao K, Hu H, Pollard JM, Goldstine J, Jung ME, Henning SM, Bertoni C, Gatti RA (2009a) Nonaminoglycoside compounds induce readthrough of nonsense mutations. The Journal of experimental medicine 206: 2285-2297 Du L, Jung ME, Damoiseaux R, Completo G, Fike F, Ku JM, Nahas S, Piao C, Hu H, Gatti RA (2013) A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Molecular therapy : the journal of the American Society of Gene Therapy 21: 1653-1660 Du M, Keeling KM, Fan L, Liu X, Bedwell DM (2009b) Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model. The Journal of biological chemistry 284: 6885-6892 Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM (2008) PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proceedings of the National Academy of Sciences of the United States of America 105: 2064-2069 Duflocq A, Le Bras B, Bullier E, Couraud F, Davenne M (2008) Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Molecular and cellular neurosciences 39: 180-192 Dutton SB, Makinson CD, Papale LA, Shankar A, Balakrishnan B, Nakazawa K, Escayg A (2013) Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiology of disease 49: 211-220 Dutton SB, Sawyer NT, Kalume F, Jumbo-Lucioni P, Borges K, Catterall WA, Escayg A (2011) Protective effect of the ketogenic diet in Scn1a mutant mice. Epilepsia 52: 2050-2056 Epstein AN, Fitzsimons JT, Rolls BJ (1970) Drinking induced by injection of angiotensin into the rain of the rat. The Journal of physiology 210: 457-474 Fang YW, Yang SS, Chau T, Nakamura M, Yamazaki O, Seki G, Yamada H, Hsu HM, Cheng CJ, Lin SH (2015) Therapeutic effect of prenatal alkalization and PTC124 in Na/HCO cotransporter 1 p.W516* knock-in mice. Gene therapy Fisher JL (2009) The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator. Neuropharmacology 56: 190-197 Francois B, Russell RJ, Murray JB, Aboul-ela F, Masquida B, Vicens Q, Westhof E (2005) Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding. Nucleic acids research 33: 5677-5690 Garrido JJ, Giraud P, Carlier E, Fernandes F, Moussif A, Fache MP, Debanne D, Dargent B (2003) A targeting motif involved in sodium channel clustering at the axonal initial segment. Science 300: 2091-2094 Gazina EV, Richards KL, Mokhtar MB, Thomas EA, Reid CA, Petrou S (2010) Differential expression of exon 5 splice variants of sodium channel alpha subunit mRNAs in the developing mouse brain. Neuroscience 166: 195-200 Genton P, Velizarova R, Dravet C (2011) Dravet syndrome: the long-term outcome. Epilepsia 52 Suppl 2: 44-49 Giraud C, Treluyer JM, Rey E, Chiron C, Vincent J, Pons G, Tran A (2006) In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug metabolism and disposition: the biological fate of chemicals 34: 608-611 Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ (2006) KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. European journal of human genetics : EJHG 14: 824-830 Goldin AL (1999) Diversity of mammalian voltage-gated sodium channels. Annals of the New York Academy of Sciences 868: 38-50 Goldin AL (2001) Resurgence of sodium channel research. Annual review of physiology 63: 871-894 Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB, Noda M, Tamkun MM, Waxman SG, Wood JN, Catterall WA (2000) Nomenclature of voltage-gated sodium channels. Neuron 28: 365-368 Goldmann T, Overlack N, Wolfrum U, Nagel-Wolfrum K (2011) PTC124-mediated translational readthrough of a nonsense mutation causing Usher syndrome type 1C. Human gene therapy 22: 537-547 Goldmann T, Rebibo-Sabbah A, Overlack N, Nudelman I, Belakhov V, Baasov T, Ben-Yosef T, Wolfrum U, Nagel-Wolfrum K (2010) Beneficial read-through of a USH1C nonsense mutation by designed aminoglycoside NB30 in the retina. Investigative ophthalmology visual science 51: 6671-6680 Gomez-Di Cesare CM, Smith KL, Rice FL, Swann JW (1997) Axonal remodeling during postnatal maturation of CA3 hippocampal pyramidal neurons. The Journal of comparative neurology 384: 165-180 Gorman AL, Marmor MF (1970) Temperature dependence of the sodium-potassium permeability ratio of a molluscan neurone. The Journal of physiology 210: 919-931 Grusser-Cornehls U, Baurle J (2001) Mutant mice as a model for cerebellar ataxia. Progress in neurobiology 63: 489-540 Gu F, Hazra A, Aulakh A, Ziburkus J (2014) Purinergic control of hippocampal circuit hyperexcitability in Dravet syndrome. Epilepsia 55: 245-255 Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O (1998) Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39: 508-512 Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, Rubenstein JL, Scheuer T, de la Iglesia HO, Catterall WA (2012) Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489: 385-390 Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH, Richards MC, Williams DA, Mulley JC, Berkovic SF, Scheffer IE, Petrou S (2002) Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. American journal of human genetics 70: 530-536 Harkin LA, McMahon JM, Iona X, Dibbens L, Pelekanos JT, Zuberi SM, Sadleir LG, Andermann E, Gill D, Farrell K, Connolly M, Stanley T, Harbord M, Andermann F, Wang J, Batish SD, Jones JG, Seltzer WK, Gardner A, Infantile Epileptic Encephalopathy Referral C, Sutherland G, Berkovic SF, Mulley JC, Scheffer IE (2007) The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain : a journal of neurology 130: 843-852 Hayashi Y, Nishiguchi S, Sydnes MO, Regnier T, Hasegawa JY, Katoh T, Kajimoto T, Node M, Kiso Y (2009) A new synthesis of (+)-negamycin and its derivatives as a potential therapeutic agent for Duchenne muscular dystrophy treatment. Advances in experimental medicine and biology 611: 137-138 Heinzen EL, Yoon W, Tate SK, Sen A, Wood NW, Sisodiya SM, Goldstein DB (2007) Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. American journal of human genetics 80: 876-883 Hernandez CC, Gurba KN, Hu N, Macdonald RL (2011) The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6beta22 and 6beta2 GABA(A) receptor channel gating and expression. The Journal of physiology 589: 5857-5878 Heron SE, Scheffer IE, Iona X, Zuberi SM, Birch R, McMahon JM, Bruce CM, Berkovic SF, Mulley JC (2010) De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin. Journal of medical genetics 47: 137-141 Horn CS, Ater SB, Hurst DL (1986) Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatric neurology 2: 340-345 Hung CC, Huang HC, Gao YH, Chang WL, Ho JL, Chiou MH, Hsieh YW, Liou HH (2012) Effects of polymorphisms in six candidate genes on phenytoin maintenance therapy in Han Chinese patients. Pharmacogenomics 13: 1339-1349 Inoue Y, Ohtsuka Y, Group STPS (2014) Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence. Epilepsy research 108: 725-731 Isom LL (2002) The role of sodium channels in cell adhesion. Frontiers in bioscience : a journal and virtual library 7: 12-23 Isom LL, Ragsdale DS, De Jongh KS, Westenbroek RE, Reber BF, Scheuer T, Catterall WA (1995) Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83: 433-442 Ito S, Ogiwara I, Yamada K, Miyamoto H, Hensch TK, Osawa M, Yamakawa K (2013) Mouse with Nav1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment. Neurobiology of disease 49: 29-40 Jonas P, Bischofberger J, Fricker D, Miles R (2004) Interneuron Diversity series: Fast in, fast out--temporal and spatial signal processing in hippocampal interneurons. Trends in neurosciences 27: 30-40 Jou SB, Kao IF, Yi PL, Chang FC (2013) Electrical stimulation of left anterior thalamic nucleus with high-frequency and low-intensity currents reduces the rate of pilocarpine-induced epilepsy in rats. Seizure 22: 221-229 Kalume F, Westenbroek RE, Cheah CS, Yu FH, Oakley JC, Scheuer T, Catterall WA (2013) Sudden unexpected death in a mouse model of Dravet syndrome. The Journal of clinical investigation 123: 1798-1808 Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA (2007) Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. The Journal of neuroscience : the official journal of the Society for Neuroscience 27: 11065-11074 Kayali R, Ku JM, Khitrov G, Jung ME, Prikhodko O, Bertoni C (2012) Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Human molecular genetics 21: 4007-4020 Kearney JA, Wiste AK, Stephani U, Trudeau MM, Siegel A, RamachandranNair R, Elterman RD, Muhle H, Reinsdorf J, Shields WD, Meisler MH, Escayg A (2006) Recurrent de novo mutations of SCN1A in severe myoclonic epilepsy of infancy. Pediatric neurology 34: 116-120 Kroll-Seger J, Portilla P, Dulac O, Chiron C (2006) Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuropediatrics 37: 325-329 Lau D, Vega-Saenz de Miera EC, Contreras D, Ozaita A, Harvey M, Chow A, Noebels JL, Paylor R, Morgan JI, Leonard CS, Rudy B (2000) Impaired fast-spiking, suppressed cortical inhibition, and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins. J Neurosci 20: 9071-9085 Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. The Journal of neuroscience : the official journal of the Society for Neuroscience 12: 4151-4172 Laux L, Blackford R (2013) The ketogenic diet in Dravet syndrome. Journal of child neurology 28: 1041-1044 Leterrier C, Brachet A, Dargent B, Vacher H (2011) Determinants of voltage-gated sodium channel clustering in neurons. Seminars in cell developmental biology 22: 171-177 Li BM, Liu XR, Yi YH, Deng YH, Su T, Zou X, Liao WP (2011) Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy behavior : E B 21: 291-295 Liautard C, Scalmani P, Carriero G, de Curtis M, Franceschetti S, Mantegazza M (2013) Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia 54: 1251-1261 Liu P, Jenkins NA, Copeland NG (2003) A highly efficient recombineering-based method for generating conditional knockout mutations. Genome research 13: 476-484 Liu YC, Cheng JK, Lien CC (2014) Rapid dynamic changes of dendritic inhibition in the dentate gyrus by presynaptic activity patterns. The Journal of neuroscience : the official journal of the Society for Neuroscience 34: 1344-1357 Lorincz A, Nusser Z (2008) Cell-type-dependent molecular composition of the axon initial segment. The Journal of neuroscience : the official journal of the Society for Neuroscience 28: 14329-14340 Lossin C (2009) A catalog of SCN1A variants. Brain development 31: 114-130 Lothman EW, Stringer JL, Bertram EH (1992) The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy research Supplement 7: 301-313 Lovick TA, Coote JH (1988) Electrophysiological properties of paraventriculo-spinal neurones in the rat. Brain research 454: 123-130 Macdonald RL, Kang JQ, Gallagher MJ (2012) GABAA Receptor Subunit Mutations and Genetic Epilepsies. In Jasper's Basic Mechanisms of the Epilepsies, Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds), 4th edn. Bethesda (MD) Mancardi MM, Striano P, Gennaro E, Madia F, Paravidino R, Scapolan S, Dalla Bernardina B, Bertini E, Bianchi A, Capovilla G, Darra F, Elia M, Freri E, Gobbi G, Granata T, Guerrini R, Pantaleoni C, Parmeggiani A, Romeo A, Santucci M, Vecchi M, Veggiotti P, Vigevano F, Pistorio A, Gaggero R, Zara F (2006) Familial occurrence of febrile seizures and epilepsy in severe myoclonic epilepsy of infancy (SMEI) patients with SCN1A mutations. Epilepsia 47: 1629-1635 Manna I, Gambardella A, Bianchi A, Striano P, Tozzi R, Aguglia U, Beccaria F, Benna P, Campostrini R, Canevini MP, Condino F, Durisotti C, Elia M, Giallonardo AT, Iudice A, Labate A, La Neve A, Michelucci R, Muscas GC, Paravidino R, Zaccara G, Zucca C, Zara F, Perucca E (2011) A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy. Epilepsia 52: e40-44 Marini C, Scheffer IE, Nabbout R, Mei D, Cox K, Dibbens LM, McMahon JM, Iona X, Carpintero RS, Elia M, Cilio MR, Specchio N, Giordano L, Striano P, Gennaro E, Cross JH, Kivity S, Neufeld MY, Afawi Z, Andermann E, Keene D, Dulac O, Zara F, Berkovic SF, Guerrini R, Mulley JC (2009) SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia 50: 1670-1678 Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A (2007) The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Human molecular genetics 16: 2892-2899 Martina M, Schultz JH, Ehmke H, Monyer H, Jonas P (1998) Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 18: 8111-8125 Mattis VB, Ebert AD, Fosso MY, Chang CW, Lorson CL (2009) Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model. Human molecular genetics 18: 3906-3913 Meisler MH, Kearney JA (2005) Sodium channel mutations in epilepsy and other neurological disorders. The Journal of clinical investigation 115: 2010-2017 Miller M (1981) Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. Journal of neurocytology 10: 859-878 Mistry AM, Thompson CH, Miller AR, Vanoye CG, George AL, Jr., Kearney JA (2014) Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiology of disease 65: 1-11 Myatt DR, Hadlington T, Ascoli GA, Nasuto SJ (2012) Neuromantic - from semi-manual to semi-automatic reconstruction of neuron morphology. Frontiers in neuroinformatics 6: 4 Nakamura K, Du L, Tunuguntla R, Fike F, Cavalieri S, Morio T, Mizutani S, Brusco A, Gatti RA (2012) Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Human mutation 33: 198-208 Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, Yamakawa K (2013) Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. Human molecular genetics 22: 4784-4804 Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, Takeuchi T, Itohara S, Yanagawa Y, Obata K, Furuichi T, Hensch TK, Yamakawa K (2007) Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience 27: 5903-5914 Ohmori I, Hayashi K, Wang H, Ouchida M, Fujita N, Inoue T, Michiue H, Nishiki T, Matsui H (2013) Inhalation of 10% carbon dioxide rapidly terminates Scn1a mutation-related hyperthermia-induced seizures. Epilepsy research 105: 220-224 Ohno Y, Ishihara S, Mashimo T, Sofue N, Shimizu S, Imaoku T, Tsurumi T, Sasa M, Serikawa T (2011) Scn1a missense mutation causes limbic hyperexcitability and vulnerability to experimental febrile seizures. Neurobiology of disease 41: 261-269 Patino GA, Claes LR, Lopez-Santiago LF, Slat EA, Dondeti RS, Chen C, O'Malley HA, Gray CB, Miyazaki H, Nukina N, Oyama F, De Jonghe P, Isom LL (2009) A functional null mutation of SCN1B in a patient with Dravet syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 29: 10764-10778 Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates, Compact 2nd edn. Amsterdam ; Boston: Elsevier Academic Press. Plummer NW, Meisler MH (1999) Evolution and diversity of mammalian sodium channel genes. Genomics 57: 323-331 Qiao X, Werkman TR, Gorter JA, Wadman WJ, van Vliet EA (2013) Expression of sodium channel alpha subunits 1.1, 1.2 and 1.6 in rat hippocampus after kainic acid-induced epilepsy. Epilepsy research 106: 17-28 Qu L, Leung LS (2008) Mechanisms of hyperthermia-induced depression of GABAergic synaptic transmission in the immature rat hippocampus. Journal of neurochemistry 106: 2158-2169 Qu L, Liu X, Wu C, Leung LS (2007) Hyperthermia decreases GABAergic synaptic transmission in hippocampal neurons of immature rats. Neurobiology of disease 27: 320-327 Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalography and clinical neurophysiology 32: 281-294 Ren D, Navarro B, Xu H, Yue L, Shi Q, Clapham DE (2001) A prokaryotic voltage-gated sodium channel. Science 294: 2372-2375 Ribak CE (1992) Local circuitry of GABAergic basket cells in the dentate gyrus. Epilepsy research Supplement 7: 29-47 Riss J, Cloyd J, Gates J, Collins S (2008) Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta neurologica Scandinavica 118: 69-86 Riva D, Vago C, Pantaleoni C, Bulgheroni S, Mantegazza M, Franceschetti S (2009) Progressive neurocognitive decline in two children with Dravet syndrome, de novo SCN1A truncations and different epileptic phenotypes. American journal of medical genetics Part A 149A: 2339-2345 Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs. Nature reviews Neuroscience 5: 553-564 Rossignol E, Lortie A, Thomas T, Bouthiller A, Scavarda D, Mercier C, Carmant L (2009) Vagus nerve stimulation in pediatric epileptic syndromes. Seizure 18: 34-37 Ryan MD, King AM, Thomas GP (1991) Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. The Journal of general virology 72 ( Pt 11): 2727-2732 Sakauchi M, Oguni H, Kato I, Osawa M, Hirose S, Kaneko S, Takahashi Y, Takayama R, Fujiwara T (2011) Mortality in Dravet syndrome: search for risk factors in Japanese patients. Epilepsia 52 Suppl 2: 50-54 Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P (2004) Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proceedings of the National Academy of Sciences of the United States of America 101: 9474-9478 Schmidt-Hieber C, Jonas P, Bischofberger J (2007) Subthreshold dendritic signal processing and coincidence detection in dentate gyrus granule cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 27: 8430-8441 Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, Salmen B, Mackie K, Sipila ST, Voipio J, Kaila K (2006) Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nature medicine 12: 817-823 Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. Journal of anatomy 87: 387-406 Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P (2011) Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia 52 Suppl 2: 95-101 Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, Cooper DN (2009) The Human Gene Mutation Database: 2008 update. Genome medicine 1: 13 Strzelczyk A, Schubert-Bast S, Reese JP, Rosenow F, Stephani U, Boor R (2014) Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam. Epilepsy behavior : E B 34: 86-91 Taguchi A, Nishiguchi S, Shiozuka M, Nomoto T, Ina M, Nojima S, Matsuda R, Nonomura Y, Kiso Y, Yamazaki Y, Yakushiji F, Hayashi Y (2012) Negamycin analogue with readthrough-promoting activity as a potential drug candidate for duchenne muscular dystrophy. ACS medicinal chemistry letters 3: 118-122 Tai C, Abe Y, Westenbroek RE, Scheuer T, Catterall WA (2014) Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. Proceedings of the National Academy of Sciences of the United States of America 111: E3139-3148 Tang B, Dutt K, Papale L, Rusconi R, Shankar A, Hunter J, Tufik S, Yu FH, Catterall WA, Mantegazza M, Goldin AL, Escayg A (2009) A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation. Neurobiology of disease 35: 91-102 Tansey EP, Chow A, Rudy B, McBain CJ (2002) Developmental expression of potassium-channel subunit Kv3.2 within subpopulations of mouse hippocampal inhibitory interneurons. Hippocampus 12: 137-148 Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB (2005) Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proceedings of the National Academy of Sciences of the United States | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54610 | - |
dc.description.abstract | Dravet症候群主要是因為嬰兒時期發生肌陣攣癲癇伴隨有心智發展的延遲以及高死亡率,由於此嚴重型癲癇的病因主要為sodium channel type I α-subunit (SCN1A) 基因產生突變導致第一型鈉離子通道 (Nav1.1) 異常。病人對目前的抗癲癇藥物常出現抗藥性而預後極差,根據美國FDA的摘錄,本疾病屬於 “未滿足之醫療需求”的範疇,因此開發新藥物為臨床醫療重要的課題,除此之外,在癲癇產生的基礎研究上,已知“海馬迴腦區”為主要癲癇形成區域之一,其齒迴區負責控制興奮性訊息進入海馬迴,但由於目前尚未有相關文獻研究因SCN1A基因突變造成海馬迴齒迴區神經網路的本質及時間上變化,特別是尚未清楚了解癲癇形成的神經網路造成發育上缺陷是否與產生癲癇行為有時程上相關性,因此,為了探討齒迴區神經網路功能性及結構上的缺陷,我建立一個帶有人類SCN1A突變點的Dravet小鼠模式 (Scn1aE1099X/+),此小鼠具有自發性癲癇以及對熱誘發癲癇有易感受度,表現型符合Dravet症候群病人的症狀,小鼠的自發性癲癇主要開始於出生後第三周,在第四周發作頻率大為提高,在這段時間,此小鼠齒迴區的表現Nav1.1的GABAergic神經元其Nav1.1表現量較其他海馬迴區域下降最多,除此之外,也發現齒迴區GABAergic神經元其動作電位之動力學改變、興奮程度降低、以及對齒迴區顆粒性細胞的抑制力下降,這些缺陷進而提高顆粒性細胞的自發性興奮訊息傳導及增加突觸前神經傳導物質釋放機率,除了電生理功能性相關的缺陷,也觀察到齒迴區顆粒性細胞的樹突型態發生異常,包括樹突結構複雜度的降低以及過多的樹突小刺,這些結構上的變化恰好與失去平衡神經網路興奮程度以及自發性癲癇高發作期於時間上重疊,因此齒迴區神經網路在結構上及功能上的發育缺陷與癲癇形成有重要的關係,同時也揭露此小鼠的神經發育過程中其神經網路連結有缺陷,更進一步推論這些結構異常可能在強化神經網路的不穩定性,使得更高層次如智力的發展受到影響,這些顯示Scn1a基因缺陷造成神經發育多方面的影響。 由於Dravet症候群在臨床上尚無良好的治療方式,目前Dravet症候群病患大多為SCN1A基因表現量不足所造成,若能以補足SCN1A表現量不足的方式進行源頭性的改善,應為較佳的治療策略,事實上在Dravet動物模式已證明提高原Scn1a表現量50%可部分改善動物的存活率由25%提高至50%,因此,在本論文的另一研究重點為開發新型藥物,目標為找到可以通讀無意義突變的異常等位基因的小分子藥物藉此提高SCN1A表現量,篩選藥物策略的獨特性為使用帶有病人突變點的小鼠cDNA後接冷光報導基因進行篩選,並由建立的小鼠平台驗證其功效,目前由Sigma LOPAC1280 library找到一化合物A具有通讀潛力,可在細胞及動物層次上再次表現蛋白,然而功能性驗證仍需更進一步驗證,若證明此化合物具通讀功能且具療效,將有機會治療各種無意義突變所導致的Dravet症候群病患,由於目前約有30%基因突變為無意義突變造成疾病,因此將有機會可推廣運用到所有由無意義突變引起的疾病。 | zh_TW |
dc.description.abstract | Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1. Current treatment of DS patients has failed due to refractory of patients to clinical available drugs. According to FDA guideline, this disease is defined as “unmet medical need.” Therefore, to develop a novel drug for the disease remains an important issue. Besides, for the basic research of the disease, the nature and timing of changes caused by SCN1A mutation in the hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus and a classic epileptogenic zone, are not well known. In particularly, it is still not clear whether the developmental deficit of this epileptogenic neural network temporally matches with the progress of seizure development. Here, we investigated the emerging functional and structural deficits of the DG network in a novel mouse model (Scn1aE1099X/+) that mimics the genetic deficit of human DS. Scn1aE1099X/+ (Het) mice, similarly to human DS patients, exhibited early spontaneous seizures and were more susceptible to hyperthermia-induced seizures starting at postnatal week (PW) 3, with seizures peaking at PW4. During the same period, the Het DG exhibited a greater reduction of Nav1.1-expressing GABAergic neurons compared to other hippocampal areas. Het DG GABAergic neurons showed altered action potential kinetics, reduced excitability, and generated fewer spontaneous inhibitory inputs into DG granule cells. The effect of reduced inhibitory input to DG granule cells was exacerbated by heightened spontaneous excitatory transmission and elevated excitatory release probability in these cells. In addition to electrophysiological deficit, we observed emerging morphological abnormalities of DG granule cells. Het granule cells exhibited progressively reduced dendritic arborization and excessive spines, which coincided with imbalanced network activity and the developmental onset of spontaneous seizures. Taken together, our results establish the existence of significant structural and functional developmental deficits of the DG network and the temporal correlation between emergence of these deficits and the onset of seizures in Het animals. Most importantly, our results uncover the developmental deficits of neural connectivity in Het mice. Such structural abnormalities likely further exacerbate network instability and compromise higher-order cognitive processing later in development, and thus highlight the multifaceted impacts of Scn1a deficiency on neural development. The current treatments for DS are unsatisfied. Most DS patients are haploinsufficiency of SCN1A. A novel therapeutic method is to increase the expression of SCN1A. According to the literature, heterozygous mice carrying Scn1a transgenes, which increase Scn1a expression levels by 50% in heterozygous mice, can partially improve the survival rate from 25% to 50%. Therefore, I propose a new therapeutic strategy: to discover and develop small molecule drugs that can read through premature terminal codons (PTC) in the mutant SCN1A allele chemically to produce sufficient Nav1.1 protein. The specificity of the strategy is using mouse Scn1a cDNA carrying human nonsense mutation to fuse with luciferase reporter gene. Compounds that can increase the luciferase will be further validated in our mouse model. By using this platform, we have identified a lead compound “compound A” from the Sigma LOPAC1280 library. Compound A can induce re-expression of the full-length Nav1.1 protein in cellular and animal models. However, the therapeutic effect still needs be determined. If the result is positive, the effective strategies will be a novel treatment for DS patients harboring nonsense mutations. Furthermore, given that ~30% of gene mutations that contribute to human diseases are nonsense mutations, our candidate compounds that can cause read-through of premature stop codons will have great potential for treating all nonsense-mutation-mediated diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T03:07:38Z (GMT). No. of bitstreams: 1 ntu-104-F96424018-1.pdf: 11882319 bytes, checksum: 54c01c76c490e3bea9d61ebdaabc40f0 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 總目錄 口試委員會審定書 I 誌謝 III 中文摘要 V 英文摘要 VII 縮寫表 IX 圖目錄 XV 表目錄 XVII 附錄目錄 XVIII 第一章 緒論 1 1.1 DRAVET SYNDROME 1 1.2 鈉離子通道簡介 2 1.2.1 鈉離子通道的結構與功能 2 1.2.2 鈉離子通道家族 3 1.3 SCN1A基因介紹及臨床病人突變點分析 4 1.3.1 人類與小鼠SCN1A基因及蛋白質表現 4 1.3.2 SCN1A表現之腦區及時程 5 1.3.3 SCN1A基因突變點分析 6 1.4 利用動物模式研究DRAVET症候群 7 1.4.1 使用動物模式研究Dravet癲癇作用機轉 7 1.4.2 使用動物模式探討Dravet症候群其他併發症 9 1.5 DRAVET 症候群的治療方法 10 1.5.1 Dravet症候群治療方式簡介 10 1.5.2抗癲癇藥物的作用機轉 10 1.5.3 Dravet症候群其他療法 12 1.6 通讀藥物開發及運用 12 1.6.1 通讀藥物簡介 12 1.6.2 通讀藥物的研究及臨床運用 13 1.7 研究動機 16 第二章 材料與方法 19 2.1 動物模式 19 2.1.1 構築Scn1aE1099X基因剔入載體及Scn1aE1099X小鼠 19 2.2 SCN1AE1099X小鼠RNA分析 20 2.2.1 小鼠腦區RNA萃取 20 2.2.2 反轉錄反應 (Reverse transcription) 21 2.2.3 即時定量聚合酶連鎖反應 (Real-time PCR) 21 2.3 西方墨點法分析 22 2.4腦電圖 (ELECTROENCEPHALOGRAPHY) 23 2.5 小鼠癲癇行為分析 23 2.5.1 自發性癲癇行為攝影記錄及分析 23 2.5.2 熱誘發性癲癇行為測量 24 2.5.3 Pentylenetetrazole誘發癲癇門檻閾值測量 24 2.6 小鼠其他行為分析 25 2.6.1 曠野實驗 (Open field test) 25 2.6.2 舉臂式十字迷宮 (Elevated plus maze) 25 2.6.3 旋轉滾筒平衡實驗 (Rotarod test) 25 2.7 免疫螢光染色 25 2.8 測量海馬迴GABA濃度 27 2.9 電生理紀錄 27 2.9.1 海馬迴腦片製備 27 2.9.2細胞內電生理紀錄 (Electrophysiological recordings) 27 2.9.3 標定神經細胞軸突形態重建 28 2.9.4 突觸前後電流紀錄 29 2.10 高基氏染色法 30 2.11 PTC124藥物製備 31 2.12 建立篩選通讀藥物的細胞平台 31 2.12.1 建構含luciferase報導基因連接具3種提前終止密碼的Scn1a DNA載體 31 2.12.2 穩定表現細胞株篩選 32 2.12.3 穩定細胞株RNA萃取及分析 33 2.12.4 穩定細胞株冷光讀值測量及分析 33 2.13 通讀藥物篩選 34 2.13.1 Sigma LOPAC1280 小分子藥物庫 34 2.13.2 小規模藥物篩選 34 2.14 以椎間給藥方式測試通讀藥物 34 2.14.1 椎間注射給藥 (Intrathecal injection) 34 2.14.2 給藥規劃 35 2.15以腦室給藥方式測試通讀藥物 35 2.15.1 腦部立體定位手術 35 2.15.2 確認留置針的位置及給藥方式 36 2.15.3 給藥規劃 36 2.16 數據分析與統計 36 第三章 研究一實驗結果 39 3.1 建立SCN1AE1099X小鼠模式 39 3.1.1 Scn1aE1099X基因於胚胎幹細胞正確互換及基因性腺遺傳 39 3.1.2 Scn1a基因、mRNA及蛋白質在Scn1aE1099X小鼠的基因型及表現量分析 39 3.2 SCN1AE1099X/+小鼠表現型分析 41 3.2.1 Scn1aE1099X/+小鼠可正常出生,但有自發性癲癇、步態不穩及100%死亡率 41 3.2.2 Scn1aE1099X/+小鼠過早死亡、自發性癲癇、及熱誘發性癲癇的高感受性 42 3.2.3 Scn1aE1099X/+小鼠的藥物誘發性癲癇門檻閾值低 44 3.2.4 Scn1aE1099X/+小鼠具高活動力的現象 45 3.3 海馬迴齒迴區的中間神經元有更顯著的NAV1.1表現量減少 46 3.4 SCN1AE1099X/+小鼠齒迴區神經網路惡化 47 3.4.1 Scn1aE1099X/+小鼠齒迴區中間神經元無法持續產生動作電位 47 3.4.2 Scn1aE1099X/+小鼠的其他離子通道無明顯的表現量變化 49 3.4.3 Scn1aE1099X/+小鼠在齒迴區選擇性提高興奮性神經傳導基礎值 49 3.5 SCN1AE1099X/+小鼠齒迴區顆粒性細胞的樹突結構複雜性降低 50 第四章 研究二之研究成果 52 4.1 建立篩選可通讀提前終止密碼藥物之細胞平台 52 4.2 建立細胞篩選通讀藥物平台 52 4.2.1 建立帶有提前終止密碼及冷光報導基因的Scn1a載體 52 4.2.2 挑選穩定細胞株做為篩藥平台 52 4.3 使用Sigma LOPAC1280小分子藥物庫篩選藥物 53 4.4 化合物A可在細胞模式表現全長NAV1.1蛋白質 54 4.5 化合物A及其衍生物可通讀三種提前終止密碼 54 4.6 化合物A可在SCN1AE1099X/E1099X小鼠再次表現蛋白 55 4.7 PTC124使用椎間注射可提高NAV1.1表現量但無法改善熱誘發癲癇門檻溫度的表現型 55 4.8 化合物A尚無法完全改善熱誘發癲癇門檻溫度 56 第五章 討論 57 5.1 SCN1AE1099X/+小鼠模式的自發性癲癇及熱誘發癲癇與其他DRAVET小鼠模式比較 57 5.2 NAV1.1減少後對發育中神經網路的影響 59 5.3 開發通讀藥物所遭遇的問題及解決方式 62 5.4 未來發展 64 參考資料: 65 圖 85 表 131 附 錄 135 個人學術簡歷 147 | |
dc.language.iso | zh-TW | |
dc.title | Dravet症候群小鼠的建立及病理分析與新藥開發之應用 | zh_TW |
dc.title | The establishment of a Dravet syndrome mouse model for pathological analysis and the application of the novel compound development | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 劉宏輝,陳佑宗,俞松良,李立仁,張芳嘉 | |
dc.subject.keyword | 小鼠模式,SCN1A,Dravet症候群,齒迴區,無意義突變,通讀藥物, | zh_TW |
dc.subject.keyword | mouse model,SCN1A,Dravet syndrome,dentate gyrus,nonsense mutation,readthrough compound, | en |
dc.relation.page | 189 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-06-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-104-1.pdf 目前未授權公開取用 | 11.6 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。