双極性障害におけるミトコンドリア機能障害に関する分子生物学的研究

• Project/Area Number: 11770536
• Research Category: Grant-in-Aid for Encouragement of Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Psychiatric science
• Research Institution: The University of Tokyo
• Principal Investigator: 加藤 忠史 東京大学, 医学部・附属病院, 講師 (30214381)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥2,300,000 (Direct Cost: ¥2,300,000); Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: 双極性障害 / カルシウム / ミトコンドリア / 躁うつ病 / 細胞内情報伝達系

Research Abstract

我々はこれまでに、双極性障害において脳エネルギー代謝異常が見られること、ミトコンドリア遺伝子の5178Cおよび10398A多型が双極性障害の危険因子となることを見出してきた。一方、双極性障害の病態には細胞内カルシウム反応の亢進が関与すると考えられていることから、患者の培養リンパ芽球を用いて、ミトコンドリアによる細胞内カルシウム制御機構を調べた。双極性障害患者および対照群より採血した末梢血液より、リンパ球を分離した。EBウイルスを用いてこれをトランスフォームし、培養した。その後、これらの細胞に、蛍光カルシウム指示薬であるFura-2およびDihydro-Rhod-2を加え、蛍光光度計を用いてPAF(血小板刺激因子)およびサプシガルギン刺激性細胞質およびミトコンドリア内カルシウム反応を調べた。PAFは容量依存性に細胞内カルシウム濃度を上昇させ、ミトコンドリア内力ルシウム濃度を低下させた。患者と健常者間で、PAFおよびサプシガルギンによる細胞質Ca^<2+>反応には差が見られなかった。しかし、プロトンイオノフォア(CCCP)でミトコンドリアCa^<2+>取り込みを失わせた後のPAF刺激では、患者群で対照群に比して有意に高い反応が見られた。これは、躁うつ病において、細胞膜のストア依存性Ca^<2+>チャネルの機能亢進、ミトコンドリアのCa^<2+>吸収能亢進などの細胞内Ca^<2+>代謝変化を示唆していると考えられた。

Research Products

• [Publications] Kato T,Kunugi H,Nanko S,Kato N: "Mitochondrial DNA polymorphisms in bipolar disorder."Journal of Affective Disorders. (in press).
• [Publications] Kato T Kunugi H,Nanko S,Kato N: "Association of bipolar disorder with the 5178 poiymorphism in mitochondrial DNA."American Journal of Medical Genetics. 96. 182-186 (2000)
• [Publications] Matsuo K,Kato T,Fukuda M,Kato N: "Alteration of hemoglobin oxygenation in the frontal region in elderly depressed patients measured by near-infrared spectroscopy."Journal of neuropsychiatry and Clinical Neuroscicences. 12. 465-471 (2000)
• [Publications] Kato T,Fujii K,Kamiya A,Kato N: "White matter hyperintensity detected bymagnetic resonance imaging and lithium response in bipolar disorder : A preliminary observation."Psychiatry and Clinical Neurosciences. 54. 117-120 (2000)
• [Publications] Murashita J,Kato T,Shioiri T,Inubshi T,Kato N: "Altered brain energymetabolism in lithium-resistant bipoloar disorder detected by photic stimulated^<31>P-MR spectroscopy."Psychological Medicine 30:107-115. 30. 107-115 (2000)
• [Publications] Kunugi H,Ishida S,Kato T,Tatsumi M,Sakai T,Hattori M,Hirose T,Nanko S: "A functional polymorphism in the promoter region of monoamine oxidase-A gene and mood disorders."Molecular Psychiatry. 4. 393-395 (1999)
• [Publications] Kato T,Honda M 他: "A novel polymorphism in the promoter region of the tumor necrosis factor alpha gene;No association with narcolepsy."American Journal of Medical Genetics. 88. 301-304 (1999)
• [Publications] Kato T,Murashita J 他: "Relationship of energy metabolism detected by ^<31>P-MRS in the human brain with mental fatigue.Neuropsvchobiology"Neuropsychobiology. 39. 214-218 (1999)
• [Publications] Kato T,Honda M 他: "A search for a mutation in the tumor necrosis factor alpha(TNF-α)gene in narcolepsy."Psychiatry and Chinical Neurosciences. 53. 421-423 (1999)
• [Publications] Kato T,Yamanaka G 他: "Efficacy of media in motivating patients with panic disorder to visit specialists."Psychiatry and Chinical Neurosciences. 53. 523-526 (1999)
• [Publications] Kunugi H,Kato T 他: "No evidence for an association of polymorphism of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients."American Jourmal of Psychiatry. 156. 774-776 (1999)
• [Publications] Murashita J,Kato T 他: "Age-dependent alteration of metabolic response to photic stimulation in the human brain measured by ^<31>PMR-spectroscopy."Brain Research. 818. 72-76 (1999)
• [Publications] Kunugi H,Kato T 他: "Dinucleotide repeat polymorphism in the neurotrophin-3 gene and hippocampal volume in psychoses."Schizophrenia Research. 37. 271-273 (1999)
• [Publications] Hamakawa H,Kato T 他: "Quantitative proton magnetic resonance spectroscopy in the bilateral frontal lobes of patients with bipolar disorder."Psychological Medicine. 29. 639-644 (1999)
• [Publications] Kunugi H,Kato T 他: "A functional polymorphism in the promoter region of monoamine oxidase-A gene and mood disorders."Molecular Psychiatry. 4. 393-395 (1999)
• [Publications] Kato T,Fujii K 他: "White matter hyperintensity detected by magnetic resonance imaging and lithium response in bipolar desorder;A preliminary observation."Psychiatry and Chinical Neurosciences. 54(in press). (2000)
• [Publications] Kato T,Kunugi H 他: "Mitochondrial DNA polymorphisms in bipolar disorder."Journal of Affective Disorders. (in press). (2000)
• [Publications] Sasaki T,Kato T 他: "Altered brain energy metabolism in lithium-resistant bipolar disorder detected by photic stimulated ^<31>P-MR spectroscopy."American Journal of Psychiatry. (in press). (2000)
• [Publications] Kato T,Kato N 他: "Mitochondrial dysfunction in bipolar disorder."Bipolar Disorder. (in press). (2000)
• [Publications] 加藤忠史: "双極性障害一躁うつ病の分子病理と治療戦略"医学書院. 201 (1999)