(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu

(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu

基本信息

  • 批准号:
    8686411
  • 负责人:
  • 金额:
    $ 38.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-06-01 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The phenothiazine group of drugs including thioridazine has been widely prescribed for the treatment of psychiatric disorders since the 1940s. The anti-cancer activities of these antipsychotics have intrigued clinicians and researchers since the early 1970s. Whereas thioridazine and several other phenothiazines can block the cardiac hERG voltage-gated potassium channels, they remain on the market because their risk for prolonging the cardiac QTc interval is outweighed by their beneficial effects. The possibility that potassium channel block is one molecular mechanism by which these antipsychotics protect against cancer has never been considered before. We propose to test the original hypothesis that thioridazine protects against medulloblastoma (MB) growth and metastasis by blocking the EAG2 voltage-gated potassium channels that are upregulated in a subset of MBs of human patients, particularly in metastatic MBs. Specifically, we hypothesize that (1) thioridazine block of EAG2 channels prevents MB cell volume reduction for premitotic condensation (PMC) so as to cause cell cycle arrest - those MB cells that venture beyond the G2 phase encounter mitotic catastrophe and perish via apoptosis, and (2) thioridazine block of EAG2 channels reduces water efflux from the trailing edge of migrating MB cells, thereby interfering with MB cell migration by preventing the trailing edge of the cell from shrinking - a local volume regulation essential for cell movement. To test our hypothesis that thioridazine block of EAG2 potassium channels that appear on the surface of mitotic MB cells and on the trailing edge of migrating MB cells to protect against MB growth and metastasis, we will conduct in vitro and in vivo studies to experimentally validate the prediction that the anti-cancer activites of thioridazine can be mimicked by pharmacological treatment with astemizole, a structurally unrelated EAG2 channel blocker. We will further test whether the anti-cancer activities of these two EAG2 channel blockers resemble the effects of reducing EAG2 expression of human MB cells in vitro and in vivo - for mice bearing human MB xenograft, as well as the effects of knocking out Eag2 in mouse MB models. Additional controls will be conducted to confirm that the anti-cancer activities of thioridazine that arise from its block of EAG2 channels are occluded by shRNA knockdown of EAG2 or genetic deletion of Eag2 in mouse models.
描述(由申请人提供):自20世纪40年代以来,包括噻嗪在内的吩噻嗪类药物已被广泛用于治疗精神疾病。自20世纪70年代初以来,这些抗精神病药物的抗癌活性引起了临床医生和研究人员的兴趣。尽管硫噻嗪和其他几种吩噻嗪类药物可以阻断心脏hERG电压门控钾通道,但它们仍然在市场上销售,因为它们延长心脏QTc间期的风险大于它们的有益作用。钾通道阻断是这些抗精神病药物预防癌症的一种分子机制,这种可能性以前从未被考虑过。我们提出通过阻断EAG2电压门控钾通道(在人类髓母细胞瘤患者中,特别是在转移性髓母细胞瘤中上调)来验证硫噻嗪对髓母细胞瘤(MB)生长和转移的原始假设。具体地说,我们假设(1)硫噻嗪阻断EAG2通道阻止MB细胞体积缩小以进行有丝分裂前冷凝(PMC),从而导致细胞周期阻滞-那些超越G2期的MB细胞遇到有丝分裂灾难并通过凋亡而死亡;(2)硫噻嗪阻断EAG2通道减少迁移MB细胞尾缘的水流出。从而通过阻止细胞的后缘收缩来干扰MB细胞的迁移-这是细胞运动所必需的局部体积调节。为了验证我们的假设,即巯基噻嗪阻断出现在有丝分裂MB细胞表面和迁移MB细胞后缘的EAG2钾通道,以保护MB的生长和转移,我们将进行体外和体内研究,实验验证巯基噻嗪的抗癌活性可以通过与结构无关的EAG2通道阻滞剂阿斯咪唑的药物治疗来模拟的预测。我们将进一步测试这两种EAG2通道阻滞剂在体外和体内对人MB异种移植小鼠的抗癌活性是否类似于降低人MB细胞EAG2表达的作用,以及在小鼠MB模型中敲除EAG2的作用。在小鼠模型中,我们将进行额外的对照,以证实硫硝嗪的抗癌活性是由其阻断EAG2通道而产生的,其抗癌活性被EAG2的shRNA敲低或EAG2的基因缺失所阻断。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

LILY Y JAN其他文献

LILY Y JAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('LILY Y JAN', 18)}}的其他基金

The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10397634
  • 财政年份:
    2021
  • 资助金额:
    $ 38.62万
  • 项目类别:
The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10221915
  • 财政年份:
    2021
  • 资助金额:
    $ 38.62万
  • 项目类别:
The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10614438
  • 财政年份:
    2021
  • 资助金额:
    $ 38.62万
  • 项目类别:
Molecular, genetic and physiological studies of calcium-activated chloride channels
钙激活氯离子通道的分子、遗传和生理学研究
  • 批准号:
    10208116
  • 财政年份:
    2020
  • 资助金额:
    $ 38.62万
  • 项目类别:
Molecular and Genetic Studies of TMEM16C Control of Thermoregulation and Neuronal Excitability
TMEM16C 控制温度调节和神经元兴奋性的分子和遗传学研究
  • 批准号:
    9885800
  • 财政年份:
    2020
  • 资助金额:
    $ 38.62万
  • 项目类别:
Central neuronal circuitry for homeostatic thermoregulation modulated by brain temperature
由脑温度调节的稳态体温调节的中枢神经元电路
  • 批准号:
    10709854
  • 财政年份:
    2020
  • 资助金额:
    $ 38.62万
  • 项目类别:
Illuminating Druggable Dark Matter
照亮可药物暗物质
  • 批准号:
    10250493
  • 财政年份:
    2017
  • 资助金额:
    $ 38.62万
  • 项目类别:
Illuminating Druggable Dark Matter
照亮可药物暗物质
  • 批准号:
    9454184
  • 财政年份:
    2017
  • 资助金额:
    $ 38.62万
  • 项目类别:
(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu
(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu
  • 批准号:
    9274826
  • 财政年份:
    2014
  • 资助金额:
    $ 38.62万
  • 项目类别:
(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu
(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu
  • 批准号:
    8856184
  • 财政年份:
    2014
  • 资助金额:
    $ 38.62万
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    $ 38.62万
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
  • 批准号:
    RGPIN-2018-04753
  • 财政年份:
    2022
  • 资助金额:
    $ 38.62万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了