Novel target deconvolution in cGAS-STING pathway
cGAS-STING 通路中的新型目标反卷积
基本信息
- 批准号:10203332
- 负责人:
- 金额:$ 10.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-02 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Immunotherapy represents a recent breakthrough in cancer treatment fueled by the accelerating mechanistic
understanding of how transformed cells subvert our immunosurveillance. Therefore, developing therapeutic
strategies that enhance systemic immunosurveillance in a controllable manner has become one of the major
interests in this field. Among different agents, small molecule activators (agonists) of the cGAS-STING
pathway have recently attracted attention because they are expected to synergize with immunotherapies and
enhance anti-cancer immune response by upregulating the interferon response.
We previously identified a compound, BDW568, that was shown to activate the interferon pathway in a
STING-dependent manner. Surprisingly, follow-up studies demonstrated that cGAS and STING are not direct
target(s) of BDW568. Therefore, observed phenotype suggests that BDW568 acts either through (1) binding
to an unknown regulator of the cGAS-STING pathway, or (2) by generating an unknown signaling molecule
independent of 2’,3’-cGAMP, the endogenous STING agonist. In the proposed study we will identify the
cellular target of BDW568 responsible for the previously discovered phenotype using two orthogonal
strategies. In the first approach, we will synthesize BDW568-based photoaffinity probes and use them to
label any protein that binds to BDW568. Labeled target(s) will be identified by a whole-cell lysate pulldown
experiments coupled with mass spectrometry (MS). In the second approach, we will use CRISPR-Cas9 to
individually knock out all the genes that are known to interact with STING or associate with interferon
pathways. The knockout of the BDW568 target should demonstrate either resistance to the compound or
elevation of the basal interferon level without BDW568 through STING. Any target candidate that emerges
from either one of these approaches will be rigorously validated according to the standards of the field to
establish that observed phenotype is due to on-target engagement. Successful completion of proposed
studies will expand the target space within cGAS-STING pathway. These insights will lead to additional
opportunities for developing adjuvant immunotherapies as well as expand our understanding of innate
immune response in mammalian cells.
免疫疗法是癌症治疗领域的最新突破,它是由加速机制推动的
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)
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Jingxin Wang其他文献
Jingxin Wang的其他文献
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{{ truncateString('Jingxin Wang', 18)}}的其他基金
Modulating gene expression by RNA-targeting chimeras
通过 RNA 靶向嵌合体调节基因表达
- 批准号:
10668510 - 财政年份:2022
- 资助金额:
$ 10.78万 - 项目类别:
Modulating gene expression by RNA-targeting chimeras
通过 RNA 靶向嵌合体调节基因表达
- 批准号:
10767095 - 财政年份:2022
- 资助金额:
$ 10.78万 - 项目类别:
Modulating gene expression by RNA-targeting chimeras
通过 RNA 靶向嵌合体调节基因表达
- 批准号:
10907204 - 财政年份:2022
- 资助金额:
$ 10.78万 - 项目类别:
Modulating gene expression by RNA-targeting chimeras
通过 RNA 靶向嵌合体调节基因表达
- 批准号:
10750002 - 财政年份:2022
- 资助金额:
$ 10.78万 - 项目类别:
Novel target deconvolution in cGAS-STING pathway
cGAS-STING 通路中的新型目标反卷积
- 批准号:
10434460 - 财政年份:2020
- 资助金额:
$ 10.78万 - 项目类别:
Novel target deconvolution in cGAS-STING pathway
cGAS-STING 通路中的新型目标反卷积
- 批准号:
10242612 - 财政年份:2012
- 资助金额:
$ 10.78万 - 项目类别:
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