The role of endoplasmic reticulum stress response in the pathophysiology of bipolar disorder

内质网应激反应在双相情感障碍病理生理学中的作用

• 批准号: 17591192
• 负责人: KUSUMI Ichiro
• 金额: $ 2.37万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591192/
• 关键词: ER stress response; Bipolar disorder; XBP1 gene; Personality traits; Lithium; Valproate; SERCA; Protein kinase C; 小胞体; Ca-ATPaseポンプ; タプシガルギン; カルモジュリン; カルシウム・ホメオスタシス; 血小板; TCI; NEO-FFI; リチウム反応性

Recently, a functional polymorphism (-116C/G) of the XBP1 gene was reported to contribute to the genetic risk factor for bipolar disorder (BPD). Moreover, the endoplasmic reticulum (ER) stress response were impaired in cultured lymphocytes from BPD patients with G allele and only valproate rescued the impairment of the ER stress response among three major mood stabilizers. In this context, it is likely that BPD patients with different genotype respond differently to mood stabilizers. Therefore, we investigated the association of-116C/G polymorphism and lithium response in patients with BPD. We found that lithium treatment is more effective in Japanese BPD patients with-116C allele carrier than in those with G allele homozygous.Disturbed intracellular calcium (Ca^<2+>) homeostasis has been implicated in BPD, which mechanisms may be involved in the dysregulation of protein kinase C (PKC) and calmodulin systems. In this study, we investigated a transient intracellular Ca^<2+> increase ind … More uced by thapsigargin, a inhibitor of sarco/endoplasmic reticulum Ca^<2+>-ATPase pump (SERCA), and a capacitative Ca^<2+> entry followed by addition of extracellular Ca^<2+>, in the presence or absence of PKC/calmodulin modulators in the platelets of healthy subjects in order to elucidate the role of SERCA in Ca^<2+> homeostasis and to assess how both PKC and calmodulin systems regulate the two Ca^<2+> responses. Moreover, we also examined the thapsigargin-elicited transient Ca^<2+> increase and capacitative Ca2+ entry in patients with mood disorders. PKC and calmodulin systems have opposite regulatory effects on the transient C^<2+> increase and capacitative Ca2+ entry in the platelets of normal subjects. The inhibitory effect of PKC activation on capacitative Ca^<2+> entry is significantly increased and the stimulatory effect of PKC inhibition is significantly decreased in BPD compared to major depressive disorder and normal controls. These results suggest the possibility that increased PKC activity may activate the inhibitory effect of capacitative Ca^<2+> entry in BPD. Less

最近，据报道 XBP1 基因的功能多态性 (-116C/G) 与双相情感障碍 (BPD) 的遗传风险因素有关。此外，来自携带G等位基因的BPD患者的培养淋巴细胞的内质网（ER）应激反应受损，并且在三种主要情绪稳定剂中，只有丙戊酸可以挽救ER应激反应的受损。在这种情况下，不同基因型的 BPD 患者对情绪稳定剂的反应可能不同。因此，我们研究了 BPD 患者的-116C/G 多态性与锂反应的关联。我们发现锂治疗对于携带-116C等位基因的日本BPD患者比携带G等位基因纯合子的患者更有效。BPD涉及细胞内钙（Ca^2+）稳态紊乱，其机制可能与蛋白激酶C（PKC）和钙调蛋白系统的失调有关。在这项研究中，我们研究了在血小板中存在或不存在 PKC/钙调蛋白调节剂的情况下，由毒胡萝卜素（一种肌浆/内质网 Ca^<2+>-ATPase 泵 (SERCA) 抑制剂）引起的短暂细胞内 Ca^<2+> 增加，以及电容性 Ca^<2+> 进入，然后添加细胞外 Ca^<2+>。 健康受试者，以阐明 SERCA 在 Ca^2+ 稳态中的作用，并评估 PKC 和钙调蛋白系统如何调节两种 Ca^2+ 反应。此外，我们还检查了心境障碍患者中毒胡萝卜素引起的短暂Ca 2+ 增加和电容性Ca 2+ 进入。 PKC和钙调蛋白系统对正常受试者血小板中短暂的C 2+ 增加和电容性Ca 2+ 进入具有相反的调节作用。与重度抑郁症和正常对照相比，BPD中PKC激活对电容性Ca 2+ 进入的抑制作用显着增加，并且PKC抑制的刺激作用显着降低。这些结果表明增加的PKC活性可能激活BPD中电容性Ca 2+ 进入的抑制作用。较少的

项目成果

Lithium response and Val66Met polymorphism of the BDNF gene in Japanese patients with bipolar disorder.

日本双相情感障碍患者的锂反应和 BDNF 基因的 Val66Met 多态性。

• 发表时间: 2006
• 期刊: Psychiatric Genetics 16
• 作者: Masui T;et al.
• 通讯作者: et al.

Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets.

丙戊酸对人血小板中血清素诱导的细胞内钙动员的影响。

• 发表时间: 2007
• 期刊: Journal of Psychiatry ＆ Neuroscience (in press)
• 作者: Akimoto T;et al.
• 通讯作者: et al.

Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI.

通过 TCI 和 NEO-FFI 评估 XBP1 基因型与人格特质之间的关系。

• 发表时间: 2005
• 期刊: Neuroscience Letter 391
• 作者: Nukina;N.;et al.;Kobayashi T;笠井慎也;Ide S;Yamamoto H;大谷保和;池田和隆;Han W;Takamatsu Y;Yamamoto H;Kasai S;Kobayashi T;下山直人;Kusumi I.
• 通讯作者: Kusumi I.

Possible association between-116C/G polymorphism of the XBP1 gene and response to lithium in bipolar disorder

XBP1 基因的 116C/G 多态性与躁郁症患者对锂的反应之间可能存在关联

• 发表时间: 2005
• 期刊: Int J Nenropsychoparmacolagy (in press)
• 作者: Kana Mizuno;Hiroyuki Okamoto;Takeshi Horio;Mizuno Kana et al.;Masui T
• 通讯作者: Masui T

A possible association between the -116C/G single nucleotide polymorphism of XBP1 gene and lithium prophylaxis in bipolar disorder.

XBP1 基因的 -116C/G 单核苷酸多态性与双相情感障碍的锂预防之间可能存在关联。

• 发表时间: 2006
• 期刊: International Journal of Neuropsychopharmacology 9
• 作者: Masui T;et al.
• 通讯作者: et al.