Systemic shRNA screens and high throughout sequencing to investigate pathway dependence in multiple myeloma
系统 shRNA 筛选和高通量测序以研究多发性骨髓瘤的通路依赖性
基本信息
- 批准号:144856378
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Clinical Research Units
- 财政年份:2009
- 资助国家:德国
- 起止时间:2008-12-31 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This central project is based on observations, that have demonstrated that different multiple myelomas (MM) differ in the activation pattern of and dependence on individual signal transduction pathways; specifically, the work has defined MMs that show activation of the Akt pathway and depend on Akt for growth and survival and a separate group of MMs that grow in an Akt-independent manner. The work raises two questions: (a) Which signal transduction pathways are critical for Akt-independent MMs? (b) Which mutations drive activation of Akt (and other critical signaling pathways in Akt-independent MMs)? To address these questions, this Z-project will pursue two strategies: first, we will develop technologies that allow functional screens to search for genes, which are critical for survival of different subtypes of multiple myeloma. To achieve this, we will adopt techniques that measure the frequency of each individual shRNA vector in a population of lentiviral shRNA vectors. We will then infect leukemic cell lines representing each subgroup with a population of such shRNA vectors (initially targeting all kinases) and measure the frequency of each vector before and after expansion in vitro and, ultimately, in vivo after transplantation of infected cells. In this manner, we will determine whether vectors targeting specific genes will be enriched or selected against during these clonal expansion of different MMs and thereby obtain information which pathways are essential for each subtype. In the first funding period, we aim to provide a proof-of-principle that such functional shRNA screens are feasible and provide clinically significant information. In a second approach, we will use the recently developed high throughput (ultra deep) sequencing technology to screen thousands of genes for the presence of potentially pathogenetically relevant (oncogenic) mutations. As a proof-of-principle, this approach will first be tested in myeloma cell lines that are investigated in parallel by shRNA screens. Thereafter, a selected set of 10 Akt-dependent and 10 Akt-independent primary MM samples as well as normal DNA from each of the patients will be sequenced to identify potential candidate mutations that may drive activation of Akt or other critical signaling pathways in Akt-independent MM.
这个中心项目是基于观察,已经证明,不同的多发性骨髓瘤(MM)不同的激活模式和依赖于个别信号转导通路;具体来说,工作已经定义了显示Akt通路的激活,并依赖于Akt的生长和生存和一个单独的组的生长Akt的独立的方式。这项工作提出了两个问题:(a)哪些信号转导途径对Akt非依赖性的转录至关重要?(b)哪些突变驱动Akt的激活(以及Akt非依赖性突变中的其他关键信号通路)?为了解决这些问题,这个Z项目将采取两种策略:首先,我们将开发技术,允许功能筛选搜索基因,这对多发性骨髓瘤的不同亚型的生存至关重要。为了实现这一点,我们将采用测量慢病毒shRNA载体群体中每个单独的shRNA载体的频率的技术。然后,我们将用一群这样的shRNA载体(最初靶向所有激酶)感染代表每个亚组的白血病细胞系,并在体外扩增前后测量每个载体的频率,并最终在受感染细胞移植后在体内测量。以这种方式,我们将确定在不同亚型的这些克隆扩增期间靶向特定基因的载体是否将被富集或选择,从而获得哪些途径对每个亚型是必需的信息。在第一个资助期,我们的目标是提供一个原理证明,这种功能性shRNA筛选是可行的,并提供临床重要信息。在第二种方法中,我们将使用最近开发的高通量(超深度)测序技术来筛选数千个基因,以确定是否存在潜在的致病相关(致癌)突变。作为原理证明,这种方法将首先在骨髓瘤细胞系中进行测试,这些细胞系通过shRNA筛选进行平行研究。此后,将对选定的一组10份Akt依赖性和10份Akt非依赖性原发性MM样本以及来自每例患者的正常DNA进行测序,以鉴定可能驱动Akt激活或Akt非依赖性MM中其他关键信号传导途径的潜在候选突变。
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 }}
Professor Dr. Martin Eilers其他文献
Professor Dr. Martin Eilers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('Professor Dr. Martin Eilers', 18)}}的其他基金
Targeting MYC-driven hepatocellular carcinoma via Aurora-A ligands
通过 Aurora-A 配体靶向 MYC 驱动的肝细胞癌
- 批准号:
409494652 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Research Units
Systematic shRNA screens for the analysis of critical signaling pathways in KRAS-mutant multiple myeloma
系统性 shRNA 筛选分析 KRAS 突变型多发性骨髓瘤的关键信号通路
- 批准号:
242271643 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Clinical Research Units
Myc-dependent apoptosis as a tumor-suppressive mechanism: how do cells discriminate between physiological and oncogenic levels of Myc expression?
Myc 依赖性细胞凋亡作为肿瘤抑制机制:细胞如何区分 Myc 表达的生理水平和致癌水平?
- 批准号:
244461114 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Research Grants
Systematic shRNA and siRNA screens to investigate drug resistance in human leukemia
系统性 shRNA 和 siRNA 筛选研究人类白血病的耐药性
- 批准号:
81569355 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Clinical Research Units
Role of Miz1 in the Atr/Chk1 signalling pathway and in Myc-induced apoptosis
Miz1 在 Atr/Chk1 信号通路和 Myc 诱导的细胞凋亡中的作用
- 批准号:
5422428 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Research Units
Rolle des Zink-Finger-Proteins Miz-1 in der Tumorigenese und in der Kontrolle der Proliferation von Keratinozyten und Lymphozyten
锌指蛋白 Miz-1 在肿瘤发生以及角质形成细胞和淋巴细胞增殖控制中的作用
- 批准号:
5340710 - 财政年份:2001
- 资助金额:
-- - 项目类别:
Research Grants
Regulation of the cdk inhibitor, p27 Regulation des cdk inhibitor, p27
cdk 抑制剂的调节,第 27 页 cdk 抑制剂的调节,第 27 页
- 批准号:
5224632 - 财政年份:1995
- 资助金额:
-- - 项目类别:
Priority Programmes
MYCN-dependent Transcription Termination and Stress Resilience of Transcription
MYCN依赖性转录终止和转录的应激恢复能力
- 批准号:
438596161 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
相似国自然基金
共载鼠尾草酸和NF-κB shRNA的关节腔靶向体系用于抗类风湿关节炎的研究
- 批准号:
- 批准年份:2024
- 资助金额:15.0 万元
- 项目类别:省市级项目
响应型MRI靶向引导温控hTERT-shRNA生成用于乳腺癌的早期精准诊疗
- 批准号:32301196
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
谷草转氨酶1(GOT1)-shRNA对大鼠肺移植急性排斥反应的影响及其机制研究
- 批准号:82160306
- 批准年份:2021
- 资助金额:34 万元
- 项目类别:地区科学基金项目
超声联合微泡介导PHD2-shRNA调控HIF-1α信号通路保护急性肾损伤的作用机制研究
- 批准号:
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
携Mig-7shRNA靶向超声微泡一体化诊疗肝癌血管生成拟态及作用机制的研究
- 批准号:82172563
- 批准年份:2021
- 资助金额:55 万元
- 项目类别:面上项目
共载shRNA-CD73及STING激动剂的纳米颗粒-静电纺丝复合缓释体系对恶性胶质瘤局部免疫治疗的作用研究
- 批准号:82172740
- 批准年份:2021
- 资助金额:55 万元
- 项目类别:面上项目
基于shRNA靶向沉默P2X3受体探讨推桥弓干预DOCA小型猪的降压机制
- 批准号:
- 批准年份:2020
- 资助金额:55 万元
- 项目类别:面上项目
构建共表达GSK-3β shRNA的三代CD19-CAR T细胞以改善弥漫大B细胞淋巴瘤化疗后患者CAR-T细胞功能的研究
- 批准号:82000196
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
新型仿生双靶向纳米药物系统携载顺铂和NOR1 shRNA联合抗肝细胞癌作用及分子机制研究
- 批准号:81971748
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
超声靶向纳泡破坏介导Gal-3shRNA转染抗心肌纤维化和左室重构的研究
- 批准号:81901769
- 批准年份:2019
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Systematic shRNA screens for the analysis of critical signaling pathways in KRAS-mutant multiple myeloma
系统性 shRNA 筛选分析 KRAS 突变型多发性骨髓瘤的关键信号通路
- 批准号:
242271643 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Clinical Research Units
Pooled shRNA screens to identify genes uniquely important for the survival and differentiation of neural cancer stem cells
汇集 shRNA 筛选以鉴定对神经癌干细胞的生存和分化特别重要的基因
- 批准号:
379219-2009 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Pooled shRNA screens to identify genes uniquely important for the survival and differentiation of neural cancer stem cells
汇集 shRNA 筛选以鉴定对神经癌干细胞的生存和分化特别重要的基因
- 批准号:
379219-2009 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Pooled shRNA screens to identify genes uniquely important for the survival and differentiation of neural cancer stem cells
汇集 shRNA 筛选以鉴定对神经癌干细胞的生存和分化特别重要的基因
- 批准号:
379219-2009 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Systematic shRNA and siRNA screens to investigate drug resistance in human leukemia
系统性 shRNA 和 siRNA 筛选研究人类白血病的耐药性
- 批准号:
91747872 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Clinical Research Units
Systematic shRNA and siRNA screens to investigate drug resistance in human leukemia
系统性 shRNA 和 siRNA 筛选研究人类白血病的耐药性
- 批准号:
81569355 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Clinical Research Units
Pooled shRNA screens for target discoveries in cancer
混合 shRNA 筛选癌症靶点发现
- 批准号:
9153918 - 财政年份:
- 资助金额:
-- - 项目类别:
CCR RNAi Initiative: Establishment of shRNA RNAi Library Screens
CCR RNAi 计划:shRNA RNAi 文库筛选的建立
- 批准号:
7592800 - 财政年份:
- 资助金额:
-- - 项目类别:
Pooled shRNA screens for target discoveries in cancer
混合 shRNA 筛选癌症靶点发现
- 批准号:
8553186 - 财政年份:
- 资助金额:
-- - 项目类别:
Pooled shRNA screens for target discoveries in cancer
混合 shRNA 筛选癌症靶点发现
- 批准号:
8763525 - 财政年份:
- 资助金额:
-- - 项目类别: