Genome-wide synthetic lethal screening for vulnerabilities in a cell model of succinate dehydrogenase-loss paraganglioma

全基因组合成致死筛查琥珀酸脱氢酶缺失副神经节瘤细胞模型中的漏洞

基本信息

  • 批准号:
    10572019
  • 负责人:
  • 金额:
    $ 22.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-08 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Abstract: Genome-wide synthetic lethal screening for vulnerabilities in a cell model of succinate dehydrogenase-loss paraganglioma This proposal focuses on the molecular pathology of familial paraganglioma (PGL). Paradoxically, this remarkable neuroendocrine cancer is caused by inherited mutations that inactivate succinate dehydrogenase (SDH), an enzyme of the mitochondrial tricarboxylic acid (TCA) cycle. A fundamental scientific understanding of the molecular basis of this tumor is lacking, limiting powerful approaches that might be identified to exploit unique vulnerabilities due to the fundamental metabolic defect in this cancer. The links between SDH loss and tissue-specific tumorigenesis remain unknown, and conventional preclinical models have been unavailable. The current hypothesis for PGL tumorigenesis invokes loss or inactivation of both parental copies of any of the four SDH subunit genes (A-D). The subsequent accumulation of succinate competitively inhibits the activities of several dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA. Despite this general mechanistic model, other mechanisms are possible and it is unclear what unique vulnerabilities may be present in SDH-loss cells that could permit targeted therapies. We hypothesize that an unbiased genome-wide lentiviral CRISPR screen will identify genes whose loss displays synthetic lethality with SDH loss. This hypothesis is supported by previous successful work in our labs identifying genes whose loss confers resistance to multiple forms of endocrine therapy in ERα+ and ERβ+ breast cancer cells. Important new PGL cell models have become available in the form of Sdhblox/lox and Sdhb-/- immortalized mouse chromaffin cells (imCC). This positions us ideally to conduct and analyze an unbiased genome-wide synthetic lethal screen using an available CRISPR single guide RNA (sgRNA) library. Aim 1 will undertake a paired unbiased lentiviral CRISPR screen in matched normal and SDH-loss imCC lines. Aim 2 will complete data analysis to identify candidate synthetic lethal genes. Aim 3 will complete independent validation of representative synthetic lethal genes and pathways. Finally, Aim 4 will implement a mouse allograft tumor model to monitor selective inhibitory effects of nominated target gene knockdown in Sdhb-/- vs. Sdhblox/lox imCC. This project is unique in being the first unbiased synthetic lethal screen addressing the unmet cancer needs of SDH-loss familial PGL patients. Because SDH genes are tumor suppressors in other cancers, including gastrointestinal stromal tumor (GIST) and some kidney cancers, identifying potential vulnerabilities in SDH-loss cells may be broadly applicable clinically.
琥珀酸盐细胞模型的全基因组合成致死筛选

项目成果

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LOUIS JAMES MAHER其他文献

LOUIS JAMES MAHER的其他文献

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{{ truncateString('LOUIS JAMES MAHER', 18)}}的其他基金

In vivo SELEX strategies to identify potent aptamer-drug conjugates for glioblastoma
体内 SELEX 策略鉴定针对胶质母细胞瘤的有效适体-药物缀合物
  • 批准号:
    10721036
  • 财政年份:
    2023
  • 资助金额:
    $ 22.3万
  • 项目类别:
Fundamental and applied studies of nucleic acids
核酸的基础与应用研究
  • 批准号:
    10323099
  • 财政年份:
    2022
  • 资助金额:
    $ 22.3万
  • 项目类别:
Fundamental and applied studies of nucleic acids
核酸的基础与应用研究
  • 批准号:
    10557080
  • 财政年份:
    2022
  • 资助金额:
    $ 22.3万
  • 项目类别:
Cell-Penetrating Aptamers Targeting Sub-Cellular Compartments
靶向亚细胞区室的细胞穿透适体
  • 批准号:
    9764414
  • 财政年份:
    2018
  • 资助金额:
    $ 22.3万
  • 项目类别:
Molecular Basis of Familial Paraganglioma
家族性副神经节瘤的分子基础
  • 批准号:
    8691748
  • 财政年份:
    2013
  • 资助金额:
    $ 22.3万
  • 项目类别:
Molecular Basis of Familial Paraganglioma
家族性副神经节瘤的分子基础
  • 批准号:
    9248912
  • 财政年份:
    2013
  • 资助金额:
    $ 22.3万
  • 项目类别:
Molecular Basis of Familial Paraganglioma
家族性副神经节瘤的分子基础
  • 批准号:
    8574656
  • 财政年份:
    2013
  • 资助金额:
    $ 22.3万
  • 项目类别:
Molecular Basis of Familial Paraganglioma
家族性副神经节瘤的分子基础
  • 批准号:
    8841328
  • 财政年份:
    2013
  • 资助金额:
    $ 22.3万
  • 项目类别:
Molecular Basis of Familial Paraganglioma
家族性副神经节瘤的分子基础
  • 批准号:
    9057471
  • 财政年份:
    2013
  • 资助金额:
    $ 22.3万
  • 项目类别:
Post-baccalaureate Training in Biomedical Research
生物医学研究学士后培训
  • 批准号:
    7882211
  • 财政年份:
    2009
  • 资助金额:
    $ 22.3万
  • 项目类别:

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新型同种异体骨软骨移植联合生长因子-胶原蛋白结合域融合技术的建立
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    $ 22.3万
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复合同种异体移植促进角膜移植的存活
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    8010394
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Augmenting Antitumor Immunity after Allografting
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    $ 22.3万
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