2000 Fiscal Year Annual Research Report

現代社会のストレス病「気分と不安」の薬理遺伝学的研究-セロトニントランスポーター遺伝子多型と病態および薬物治療アルゴリズム-

Research Project

Project/Area Number	12558089
Research Institution	Kobe University
Principal Investigator	斎藤尚亮神戸大学, バイオシグナル研究センター, 教授 (60178499)
Co-Investigator(Kenkyū-buntansha)	佐野輝愛媛大学, 医学部, 助教授 (30178800)
Keywords	セロトニントランスポーター / 遺伝子解析 / 遺伝子多型 / 気分・不安性障害 / プロモーター / レポーターアッセイ
Research Abstract	1)マウスセロトニントランスポーター遺伝子発現調節機構の解析マウスセロトニントランスポーター遺伝子の上流領域の解析により、少なくとも3つの転写開始点が存在することを明らかにした。それぞれの転写開始点のプロモーター部位を単離し、レポーター遺伝子を含むベクタ-プラスミドに組み込み、レポーター遺伝子活性を測定することで、プロモーターを測定した。また、種々の細胞における各プロモーター活性、および各プロモーター活性に対する各種薬物の影響を解析した。その結果、細胞種によって、プロモーター活性が異なること、また、転写調節因子(CREBなど)による調節機構が異なることを見出した。 2)ヒトセロトニントランスポーター遺伝子多型の機能解析セロトニントランスポーター遺伝子発現調節部位の11種類の遺伝子多型(14-22回のRepeat配列:5-HTTLPR多型)の機能相関を評価するため、レポーター遺伝子を含むベクタ-プラスミドに各対立遺伝子断片を組み込み、褐色細胞種由来細胞、サル線維芽細胞、マウス背側縫線核由来細胞などにトランスフェクションし、レポーター遺伝子活性を測定することで、プロモーターおよびエンハンサー活性を評価した。その結果、ヒトセロトニントランスポーター遺伝子多型(5-HTTLPR多型)部位はサイレンサーとして機能し、その活性は、大きく3つのグループに分類されることが明らかになった。今後、健常対照群および気分・不安性障害患者群を対象として、この遺伝子多型(5-HTTLPR多型)解析結果を臨床データと突き合わせた総合的統計解析を施行し、疾患関連性、薬物反応関連性を検討する予定である。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Kajimoto,T.: "Subtype-specific translocation of δ-PKC and its activation by tyrosine phosphorylation induced by ceramide in HeLa cells."Mol.Cell.Biol.. (印刷中). (2001)
[Publications] Ohmori.S.: "Importance of PKC targeting for the phosphorylation of its substrate.myristoylated alanine-rich C-kinase substrate (MARCKS)."J.Biol.Chem.. 275. 26449-26457 (2000)
[Publications] Shirai,Y.: "Subtype-specific translocation of diacylglycerol kinase α and γ and its correlation with protein kinase C."J.Biol.Chem.. 275. 24760-24766 (2000)
[Publications] Larsen,E.C.: "Differential requirement for classic and novel PKC isoforms in respiratory burst and phagocytosis in RAW 264.7 cells."J.Immunol.165. 2809-2817 (2000)
[Publications] Shirai,Y.: "Phospholipase A2 and its products are involved in the purinergic receptor-mediated translocation of protein kinase C in CHO-Kl cells."J.Cell Sci.. 113. 1335-1343 (2000)
[Publications] Sumioka,K.: "Induction of 55 kDa PKN cleavage product by ischemia/reperfusion model in the rat retina."Invest.Opthal.Vis.Sci.,. 41. 29-35 (2000)
[Publications] Kondoh,T.: "In vivo gene transfer into periventricular region by electroporation."Neurologia medico-chirurgica.. 40. 618-623 (2000)
[Publications] Sakai,N.: "Involvement of the actin cytoskeleton in the regulation of scrotonin transporter (SET) activity : possible mechanism underlying SET regulation by protein kinase C."Neurochem.Int.. 36. 567-579 (2000)
[Publications] Oyasu,M.: "Immunocytochemical localization of a neuron-specific thromhospondin-1-like protein.NELL2 : Light and electron microscopic studies in the rat brain."Mol.Brain Res.. 76. 151-160 (2000)
[Publications] Yokogawa,T.: "Evidence that 3'-phosphorylated polyphosphoinositides are generated at the nuclear surface : use off immunostaining technique with monoclonal antibodies specific for P13.4-P2"FEBS Lett.. 473. 222-226 (2000)
[Publications] Akiyama,H.: "Blood-brain barrier formation of grafted human umbilical vein endothelial cells in athymic mouse brain."Brain Res.. 858. 172-176 (2000)
[Publications] Ucyama,T.: "cDNA cloning of an alternative splicing variant of protein kinase Cδ(PKCδIII).a new truncated form of PKCδ,in rats."Biochem.Biophys.Res.Commun.. 269. 557-563 (2000)
[Publications] Nakagawa,N.: "ENH.containing PDZ and LIM domain, heart/skeletal muscle-specific protein, associates with cytoskeletal protein through its PDZ domain."Biochem.Biophys.Res.Commun.. 272. 505-512 (2000)
[Publications] Shibaguchi,H.: "Role of synaptophysin in exocytic release of dopamine from Xenopus oocytes injected with rat brain mRNA."Cellulat and Molecular Neurobiology.. 20. 401-408 (2000)
[Publications] Nakai,M.: "Amyloidβ protein activates PKC-δ and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia."Neurochem.Int.. (印刷中).
[Publications] Nakamura,M.: "The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants."Mol.Psychiat.. 5. 32-38 (2000)
[Publications] Foley,P.: "The L-DOPA story-an early Japanese contribution."Parkinsonism & Related Disorders. 6. 1-6 (2000)
[Publications] 佐野輝: "抗不安薬・催眠薬."CLINICAL NEUROSCIENCE. 19(2). 234-235 (2001)

2000 Fiscal Year Annual Research Report

現代社会のストレス病「気分と不安」の薬理遺伝学的研究-セロトニントランスポーター遺伝子多型と病態および薬物治療アルゴリズム-

Principal Investigator

斎藤 尚亮 神戸大学, バイオシグナル研究センター, 教授 (60178499)

Research Products

[Publications] Kajimoto,T.: "Subtype-specific translocation of δ-PKC and its activation by tyrosine phosphorylation induced by ceramide in HeLa cells."Mol.Cell.Biol.. (印刷中). (2001)

[Publications] Ohmori.S.: "Importance of PKC targeting for the phosphorylation of its substrate.myristoylated alanine-rich C-kinase substrate (MARCKS)."J.Biol.Chem.. 275. 26449-26457 (2000)

[Publications] Shirai,Y.: "Subtype-specific translocation of diacylglycerol kinase α and γ and its correlation with protein kinase C."J.Biol.Chem.. 275. 24760-24766 (2000)

[Publications] Larsen,E.C.: "Differential requirement for classic and novel PKC isoforms in respiratory burst and phagocytosis in RAW 264.7 cells."J.Immunol.165. 2809-2817 (2000)

[Publications] Shirai,Y.: "Phospholipase A2 and its products are involved in the purinergic receptor-mediated translocation of protein kinase C in CHO-Kl cells."J.Cell Sci.. 113. 1335-1343 (2000)

[Publications] Sumioka,K.: "Induction of 55 kDa PKN cleavage product by ischemia/reperfusion model in the rat retina."Invest.Opthal.Vis.Sci.,. 41. 29-35 (2000)

[Publications] Kondoh,T.: "In vivo gene transfer into periventricular region by electroporation."Neurologia medico-chirurgica.. 40. 618-623 (2000)

[Publications] Sakai,N.: "Involvement of the actin cytoskeleton in the regulation of scrotonin transporter (SET) activity : possible mechanism underlying SET regulation by protein kinase C."Neurochem.Int.. 36. 567-579 (2000)

[Publications] Oyasu,M.: "Immunocytochemical localization of a neuron-specific thromhospondin-1-like protein.NELL2 : Light and electron microscopic studies in the rat brain."Mol.Brain Res.. 76. 151-160 (2000)

[Publications] Yokogawa,T.: "Evidence that 3'-phosphorylated polyphosphoinositides are generated at the nuclear surface : use off immunostaining technique with monoclonal antibodies specific for P13.4-P2"FEBS Lett.. 473. 222-226 (2000)

[Publications] Akiyama,H.: "Blood-brain barrier formation of grafted human umbilical vein endothelial cells in athymic mouse brain."Brain Res.. 858. 172-176 (2000)

[Publications] Ucyama,T.: "cDNA cloning of an alternative splicing variant of protein kinase Cδ(PKCδIII).a new truncated form of PKCδ,in rats."Biochem.Biophys.Res.Commun.. 269. 557-563 (2000)

[Publications] Nakagawa,N.: "ENH.containing PDZ and LIM domain, heart/skeletal muscle-specific protein, associates with cytoskeletal protein through its PDZ domain."Biochem.Biophys.Res.Commun.. 272. 505-512 (2000)

[Publications] Shibaguchi,H.: "Role of synaptophysin in exocytic release of dopamine from Xenopus oocytes injected with rat brain mRNA."Cellulat and Molecular Neurobiology.. 20. 401-408 (2000)

[Publications] Nakai,M.: "Amyloidβ protein activates PKC-δ and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia."Neurochem.Int.. (印刷中).

[Publications] Nakamura,M.: "The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants."Mol.Psychiat.. 5. 32-38 (2000)

[Publications] Foley,P.: "The L-DOPA story-an early Japanese contribution."Parkinsonism & Related Disorders. 6. 1-6 (2000)

[Publications] 佐野輝: "抗不安薬・催眠薬."CLINICAL NEUROSCIENCE. 19(2). 234-235 (2001)

斎藤尚亮神戸大学, バイオシグナル研究センター, 教授 (60178499)