(PQB3) Investigating innate immunosurveillance of oncogene-induced danger signals
(PQB3) 研究癌基因诱导的危险信号的先天免疫监视
基本信息
- 批准号:8686200
- 负责人:
- 金额:$ 32.52万
- 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:2014-05-16 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanAntigensAutomobile DrivingBypassCancer PatientCellsDevelopmentDiseaseDisease ProgressionEarly DiagnosisEpigenetic ProcessEventGenesGeneticGenetically Engineered MouseHumanImmuneImmune responseImmune systemImmunologic MonitoringImmunotherapeutic agentIn VitroIntrinsic factorLeadLeftLesionLigandsLung AdenocarcinomaLung NeoplasmsMalignant - descriptorMalignant NeoplasmsMediatingModelingMolecularMouse StrainsMusMuscle CellsMutagenesisMutateMutationNatural Killer CellsNeoplastic Muscle CellNormal CellOncogenesOncogenicOutcomePopulationProcessProductionPublic HealthRecruitment ActivityRegulationRoleSignal TransductionStagingStreamSystemT cell responseT-LymphocyteTestingTissuesTumor AntigensTumor PromotionUncertaintyVirus Diseasescell transformationcell typechemokinecostcytokineimmune activationimmune clearanceimmunogenicin vivolung sarcomametaplastic cell transformationmouse modelneoplasticneoplastic cellnovelpreventpublic health relevanceresearch studyresponsesarcomasenescencesmall hairpin RNAtumortumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): Cancer immunosurveillance is a potential mechanism for immune recognition and elimination of pre-emergent tumor cells, but little is known about the tumor cell-derived danger signals that drive immunosurveillance. Genetically engineered mouse models (GEMMs) recapitulate cardinal features of human cancers, including interactions between tumor cells and their microenvironment, and have helped uncover complexities underlying tumor development. We have previously used GEMMs to identify similarities and differences between lung adenocarcinoma and sarcoma development. Expression of oncogenic KrasG12D by muscle cells activates a genetic circuit involving p19 (Arf) and p53 that promotes arrest and stops tumor development. By contrast, lung tumors bypass this genetic circuit by epigenetically silencing p19 (Arf). In advanced tumor cells, signals down-stream of p53 also trigger arrest and mediate elimination by NK and other innate immune cells. The fate of KrasG12D-arrested muscle cells is unclear, but immunosurveillance and elimination by innate immune cells could reduce the chances these pre-neoplastic cells acquire additional genetic alterations and develop into sarcomas. In Aim 1 of this application, we will directly investigate the role of innate immune cells in detecting and clearing pre-neoplastic cells in a mouse model in which the events controlling the initial acquisition of oncogenic K-rasG12D are independent of those controlling p53 deletion (required for release from an arrested state). Additionally, we will
test whether NK cells can augment and/or inhibit clearance by expressing activating and inhibitory ligands in these lesions. The comparison of KrasG12D expressing p53-deficient sarcomas and lung adenocarcinomas provides a powerful platform for investigating how early events in tumorigenesis determine whether anti-tumor T cell responses are protective in vivo. Despite tumor development in identical mice, with identical initiating genetic alterations, expressing identical tumor antigens, and eliciting responses from identical populations of naive T cells, antigen-expressing lung adenocarcinomas develop in mice while antigen- expressing sarcomas do not. In Aim 2, we will compare early innate immune responses to sarcomas and lung adenocarcinomas and determine how environmental and cell-intrinsic responses to transformation contribute to innate activation and anti-tumor T cell responses. In Aim 3, we will identify the mechanisms by which immune cells become alerted to the presence of pre-neoplastic and fully transformed tumor cells and whether knockdown of danger signals can help pre-emergent tumors subvert immunosurveillance mechanisms and grow in vivo. These Aims will strengthen our understanding of the molecular and cellular events that regulate immunosurveillance at the earliest stages of malignant transformation and help us to understand why certain tumor types are more immunogenic as a result.
描述(由申请人提供):癌症免疫监视是一种免疫识别和消除发射前肿瘤细胞的潜在机制,但对驱动免疫监视的肿瘤细胞衍生的危险信号知之甚少。基因工程的小鼠模型(GEMM)概括了人类癌症的基本特征,包括肿瘤细胞及其微环境之间的相互作用,并帮助发现了肿瘤发展的基础复杂性。我们以前已经使用GEMM来确定肺腺癌和肉瘤发育之间的相似性和差异。肌肉细胞对致癌性Krasg12d的表达激活了涉及p19(ARF)和p53的遗传回路,从而促进停滞并阻止肿瘤发育。相比之下,肺肿瘤通过表观遗传沉默的P19(ARF)绕过这一遗传回路。在晚期肿瘤细胞中,p53的信号还会引发NK和其他先天免疫细胞的抑制和介导消除。 KRASG12D降落的肌肉细胞的命运尚不清楚,但是先天免疫细胞的免疫监测和消除可以减少这些肿瘤前细胞的机会,从而获得了额外的遗传改变并发展为肉瘤。在本应用的AIM 1中,我们将直接研究先天免疫细胞在检测和清除小鼠模型中检测和清除肿瘤前细胞的作用,在小鼠模型中,控制了控制致癌k-rasg12d的初始获取的事件与控制p53缺失的事件无关(从释放中释放了p53)。此外,我们会的
测试NK细胞是否可以通过在这些病变中表达激活和抑制性配体来增加和/或抑制清除率。表达p53缺陷肉瘤和肺腺癌的KRASG12D的比较为研究肿瘤发生的早期事件如何确定抗肿瘤T细胞反应在体内是否具有保护性。尽管相同小鼠的肿瘤发育,但同一引发遗传改变,表达相同的肿瘤抗原,并引起相同的幼稚T细胞群体的反应,但表达抗原的抗原抗原的抗原表达抗原的抗原腺癌的反应却没有。在AIM 2中,我们将比较对肉瘤和肺腺癌的早期先天免疫反应,并确定环境和细胞中性反应如何对转化的环境和细胞中心反应有助于先天激活和抗肿瘤T细胞反应。在AIM 3中,我们将确定免疫细胞被警告的机制,以警告肿瘤前和完全转化的肿瘤细胞,以及危险信号的敲低是否可以帮助爆发前的肿瘤颠覆免疫监视机制并在体内生长。这些目标将加强我们对在恶性转化最早调节免疫监视的分子和细胞事件的理解,并帮助我们理解为什么某些肿瘤类型因此更具免疫原性。
项目成果
期刊论文数量(0)
专著数量(0)
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TYLER E. JACKS其他文献
TYLER E. JACKS的其他文献
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{{ truncateString('TYLER E. JACKS', 18)}}的其他基金
Studying factors controlling cancer progression and immune recognition in mouse models
研究小鼠模型中控制癌症进展和免疫识别的因素
- 批准号:
10707303 - 财政年份:2022
- 资助金额:
$ 32.52万 - 项目类别:
Development of novel metastatic mouse models that recapitulate the major immune contexts of human colon cancer
开发新的转移性小鼠模型来概括人类结肠癌的主要免疫环境
- 批准号:
9887423 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
Development of novel metastatic mouse models that recapitulate the major immune contexts of human colon cancer
开发新的转移性小鼠模型来概括人类结肠癌的主要免疫环境
- 批准号:
10304921 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
Development of novel metastatic mouse models that recapitulate the major immune contexts of human colon cancer
开发新的转移性小鼠模型来概括人类结肠癌的主要免疫环境
- 批准号:
10063490 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
(PQB3) Investigating innate immunosurveillance of oncogene-induced danger signals
(PQB3) 研究癌基因诱导的危险信号的先天免疫监视
- 批准号:
8849870 - 财政年份:2014
- 资助金额:
$ 32.52万 - 项目类别:
(PQB6)Elucidating metastasis by real-time monitoring and tagging of CTCs in GEMMs
(PQB6)通过实时监测和标记 GEMM 中的 CTC 来阐明转移
- 批准号:
8836990 - 财政年份:2014
- 资助金额:
$ 32.52万 - 项目类别:
(PQB6)Elucidating metastasis by real-time monitoring and tagging of CTCs in GEMMs
(PQB6)通过实时监测和标记 GEMM 中的 CTC 来阐明转移
- 批准号:
8686204 - 财政年份:2014
- 资助金额:
$ 32.52万 - 项目类别:
(PQB6)Elucidating metastasis by real-time monitoring and tagging of CTCs in GEMMs
(PQB6)通过实时监测和标记 GEMM 中的 CTC 来阐明转移
- 批准号:
9330805 - 财政年份:2014
- 资助金额:
$ 32.52万 - 项目类别:
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