Activating Bax as a therapeutic strategy for lung cancer

激活 Bax 作为肺癌的治疗策略

基本信息

  • 批准号:
    8479579
  • 负责人:
  • 金额:
    $ 31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However, many of these strategies target the interaction among various Bcl-2 proteins, particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins, these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein, Bax s involved in the development of tumors, and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigms, direct activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax, leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore, we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax, induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development, inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.
描述(申请人提供):大多数人类癌细胞对凋亡具有抵抗力。在细胞凋亡的主要调节因子中,有一种是Bcl2蛋白家族。一种新兴的癌症治疗策略是通过抑制抗凋亡的Bcl2蛋白的活性或促进促凋亡的Bcl2蛋白的功能来直接激活凋亡途径。然而,这些策略中的许多都是针对不同的Bcl2蛋白之间的相互作用,特别是促凋亡和抗凋亡的Bcl2蛋白之间的相互作用。由于Bcl2蛋白之间的功能冗余,这些方法可能只对有限的肿瘤类型有效或显示非特异性杀伤活性。作为一种重要的促凋亡蛋白,Bax S参与了肿瘤的发生发展过程,而Bax的激活与肺癌细胞的凋亡密切相关。鉴于BAX本身足以在几乎所有的凋亡范例中启动凋亡, 小分子化合物直接激活Bax可诱导表达Bax的肿瘤细胞死亡。我们在大型化学文库的电子筛选中的初步研究确定了一个预测与Bax疏水沟槽结合的小分子。该化合物能够激活Bax,导致Bax依赖的肿瘤细胞凋亡,抑制小鼠肿瘤生长。具体目的如下:1)研究Bax激活剂抑制小鼠肿瘤生长的机制。我们将测试Bax激活剂对小鼠移植人肿瘤和自发性小鼠肺肿瘤生长的抑制能力。此外,我们还将研究该活性化合物是否与其他治疗药物协同作用,以抑制肿瘤的生长。2)提高Bax激活剂激活Bax、诱导细胞凋亡和抑制肿瘤生长的能力。基于配基的分析将用于识别具有更大生物活性的潜在化合物,并将对这些化合物进行实验研究。3)探讨了Bax激活剂在生物膜上活化Bax的机理。我们将使用一种新的膜片钳技术,结合生化和细胞生物学的方法来研究Bax激活剂如何在体外诱导天然生物膜上的Bax渗透通道。我们还将研究Bax渗透孔的形成是如何受到抗凋亡蛋白Bclxl的调节的。由于Bax表达异常与肺癌的发生发展有关,通过直接激活Bax诱导肿瘤细胞凋亡有望成为治疗肺癌的一种新的治疗策略。

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(2)

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 }}

Chi Li其他文献

Chi Li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('Chi Li', 18)}}的其他基金

A lung cancer vaccine based on exosomes of induced pluripotent stem cells
基于诱导多能干细胞外泌体的肺癌疫苗
  • 批准号:
    10651014
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
A Stem Cell Based Exosomal Vaccine for the Prevention of Cancer
用于预防癌症的基于干细胞的外泌体疫苗
  • 批准号:
    10577271
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
Activating Bax as a therapeutic strategy for lung cancer
激活 Bax 作为肺癌的治疗策略
  • 批准号:
    8849866
  • 财政年份:
    2013
  • 资助金额:
    $ 31万
  • 项目类别:
Activating Bax as a therapeutic strategy for lung cancer
激活 Bax 作为肺癌的治疗策略
  • 批准号:
    9283319
  • 财政年份:
    2013
  • 资助金额:
    $ 31万
  • 项目类别:
COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
COBRE 项目 6:从内质网启动的程序性死亡途径
  • 批准号:
    8360667
  • 财政年份:
    2011
  • 资助金额:
    $ 31万
  • 项目类别:
COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
COBRE 项目 6:从内质网启动的程序性死亡途径
  • 批准号:
    8167779
  • 财政年份:
    2010
  • 资助金额:
    $ 31万
  • 项目类别:
COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
COBRE 项目 6:从内质网启动的程序性死亡途径
  • 批准号:
    7959807
  • 财政年份:
    2009
  • 资助金额:
    $ 31万
  • 项目类别:
Regulation of apoptosis by Bcl-XL, Bak and Bax
Bcl-XL、Bak 和 Bax 对细胞凋亡的调节
  • 批准号:
    7921271
  • 财政年份:
    2009
  • 资助金额:
    $ 31万
  • 项目类别:
COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
COBRE 项目 6:从内质网启动的程序性死亡途径
  • 批准号:
    7720767
  • 财政年份:
    2008
  • 资助金额:
    $ 31万
  • 项目类别:
COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
COBRE 项目 6:从内质网启动的程序性死亡途径
  • 批准号:
    7610539
  • 财政年份:
    2007
  • 资助金额:
    $ 31万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 31万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 31万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 31万
  • 项目类别:
    Studentship
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 31万
  • 项目类别:
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 31万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 31万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了