Precision targeting of bladder cancer using CRISPR technology
Precision targeting of bladder cancer using CRISPR technology
批准号:
10442573
负责人:
MATS LJUNGMAN
金额:
$21.44万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-07-01 至 2023-06-30
关键词:
Automobile DrivingBenchmarkingBioluminescenceCRISPR/Cas technologyCancer ModelCancer cell lineCellsChemistryChromosome PairingChromosomesClinicClinicalClustered Regularly Interspaced Short Palindromic RepeatsColon CarcinomaComplexDNA Double Strand BreakDNA Sequence AlterationData SetDevelopmentDrug DesignDrug TargetingElementsEncapsulatedGene DosageGenerationsGrowthGuide RNAIn VitroMalignant NeoplasmsMalignant neoplasm of urinary bladderMonitorMusOncogenesOncogenicPathway interactionsPharmaceutical PreparationsPrecision therapeuticsProteinsRNAReagentSiteSystemTechnologyTestingTherapeuticTimeTumor BiologyTumor BurdenTumor Suppressor GenesXenograft procedurebasecancer cellcancer typecarcinogenesisdesignendonucleasegenome sequencingin vivolipid nanoparticlemouse modelmultidisciplinarynanoparticlenanoparticle deliveryneoplastic cellnovelnovel strategiespersonalized approachpre-clinicalprotein complextargeted cancer therapytumorwhole genome
中文摘要
摘要
染色体重排在癌症中很常见,通常发生在癌发生的早期。
它们通过改变癌基因和肿瘤细胞的表达或功能来驱动肿瘤的发展。
抑制基因的拷贝数改变,形成致癌融合或改变
负责调节癌症基因的DNA元件。尽管这是一个众所周知的特点,
癌症,发现超过一百年前,这种常见的癌症标志还没有
治疗性剥削现在,第一次,整个基因组的技术进步
测序和CRISPR技术的发展使其成为精确靶向的技术,
可以识别和靶向肿瘤细胞中的染色体重排连接(CRJ)。在
此外,最近在涉及纳米颗粒的CRIPR试剂的体内递送方面的突破将
为临床应用开辟了新的途径。在这个R21应用中,我们提出了一种精确的CRISPR,
一种旨在靶向癌症特异性CRJ的方法,
所有肿瘤这种基于CRISPR的精确方法由成对的CRJ靶向指导RNA组成
(gRNA)将dCas 9缀合的内切核酸酶Fok 1的两个部分结合在一起,导致其
激活和诱导致死性DNA双链断裂(DSB),特别是在癌细胞中。
无论肿瘤驱动机制如何,CRJ的存在将被利用来选择性地
迫使这些癌细胞死亡。我们已经获得了成功瞄准的原理证明,
在结肠癌和膀胱癌细胞系中使用这种方法的CRJ。我们已经建立了一个多-
拥有CRISPR技术和设计、脂质纳米粒递送等专业知识的学科团队
系统和膀胱癌小鼠模型。有了这个团队,有了强有力的证据,
在癌细胞系中用Fok 1-dCas 9有效靶向CRJ,我们现在准备开发
并使用最近开发的突破性脂质在临床前癌症模型中测试我们的方法
纳米粒子输送技术。如果成功实施,这种范式转换的精度-
靶向癌症治疗平台可能在设计统一的治疗方法方面具有变革性,
所有癌症类型,无论肿瘤的生物学。
英文摘要
ABSTRACT
Chromosome rearrangements are common in cancers and typically occur early in carcinogenesis.
They drive tumor development by altering the expression or function of oncogenes and tumor
suppressor genes by copy number alterations, formation of oncogenic fusions or by alterations of
DNA elements responsible for regulating cancer genes. Despite being a well-known feature of
cancer, discovered over hundred years ago, this common cancer hallmark has not yet been
therapeutically exploited. Now, for the first time, technological advancements in whole genome
sequencing and the development of CRISPR technologies for precision targeting makes it
possible to identify and target chromosome rearrangement junctions (CRJs) in tumor cells. In
addition, recent breakthroughs in in vivo delivery of CRIPR reagents involving nanoparticles will
open new avenues into clinical utilization. In this R21 application, we present a precision CRISPR
approach that aims at targeting cancer-specific CRJs as an untapped Achilles heel common to
all tumors. This CRISPR-based precision approach consists of pairs of CRJ-targeting guide RNAs
(gRNAs) that bring together two parts of a dCas9-conjugated endonuclease, Fok1, leading to its
activation and the induction of lethal DNA double strand breaks (DSBs) specifically in cancer cells.
Regardless of the tumor-driving mechanism, the presence of CRJs will be exploited to selectively
force these cancer cells to die. We have obtained proof-of-principle of the successful targeting of
CRJs with this approach in both colon and bladder cancer cell lines. We have assembled a multi-
disciplinary team with expertise in CRISPR technology and design, lipid nanoparticle delivery
systems and bladder cancer mouse models. With this team in place and with strong evidence of
efficient targeting of CRJs with Fok1-dCas9 in cancer cell lines, we are now primed to develop
and test our approach in pre-clinical cancer models using recently developed breakthrough lipid
nanoparticle delivery technologies. If successfully implemented, this paradigm-shifting precision-
targeting cancer therapeutic platform could be transformative in designing uniform treatments for
all cancer types irrespective of the biology of the tumor.
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会议论文
Career Enhancement Program
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批准号:10554480
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资助金额:$9.57万
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财政年份:2023
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Mapping of Novel Candidate Functional Elements with Bru-Seq Technology
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批准号:10240972
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资助金额:$46.05万
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财政年份:2021
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负责人:MATS LJUNGMAN
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依托单位:
Precision targeting of bladder cancer using CRISPR technology
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批准号:10289763
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项目类别:
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资助金额:$18.23万
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财政年份:2021
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负责人:MATS LJUNGMAN
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依托单位:
Targeting the RNA Exosome for Cancer Therapeutics
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批准号:10684671
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项目类别:
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资助金额:$47.96万
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财政年份:2019
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负责人:MATS LJUNGMAN
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依托单位:
Targeting the RNA Exosome for Cancer Therapeutics
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批准号:10208799
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项目类别:
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资助金额:$48.94万
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财政年份:2019
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负责人:MATS LJUNGMAN
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依托单位:
Targeting the RNA Exosome for Cancer Therapeutics
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批准号:10462596
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项目类别:
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资助金额:$47.96万
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财政年份:2019
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负责人:MATS LJUNGMAN
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依托单位:
Mapping of Novel Candidate Functional Elements with Bru-Seq Technology
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批准号:9246747
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资助金额:$47.97万
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财政年份:2017
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负责人:MATS LJUNGMAN
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依托单位:
Travel Awards for the 4th Asian Conference on Environmental Mutagens
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批准号:8837932
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项目类别:
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资助金额:$1.0万
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财政年份:2014
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负责人:MATS LJUNGMAN
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依托单位:
2013 Environmental Mutagen Society Annual Meeting
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批准号:8856573
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项目类别:
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资助金额:$1.2万
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财政年份:2013
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负责人:MATS LJUNGMAN
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依托单位:
2013 Environmental Mutagen Society Annual Meeting
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批准号:8737903
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项目类别:
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资助金额:$1.2万
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财政年份:2013
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负责人:MATS LJUNGMAN
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依托单位:
2013 Environmental Mutagen Society Annual Meeting
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批准号:8594353
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项目类别:
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资助金额:$1.2万
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财政年份:2013
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负责人:MATS LJUNGMAN
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依托单位:
Development and Validation of BruChase-Seq and BrUV-Seq
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批准号:8464184
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项目类别:
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资助金额:$37.25万
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财政年份:2012
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负责人:MATS LJUNGMAN
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依托单位:
Development and Validation of BruChase-Seq and BrUV-Seq
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批准号:8310663
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项目类别:
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资助金额:$39.01万
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财政年份:2012
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负责人:MATS LJUNGMAN
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依托单位:
Development and Validation of BruChase-Seq and BrUV-Seq
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批准号:8628859
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项目类别:
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资助金额:$38.23万
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财政年份:2012
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负责人:MATS LJUNGMAN
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依托单位:
Mechanisms of Genotoxic Stress-regulated Gene Expression in Human Cells
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批准号:8462978
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资助金额:$19.05万
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负责人:MATS LJUNGMAN
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Environmental Mutagen Society 2012 Annual Meeting-Trainee and Speaker Support
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Mechanisms of Genotoxic Stress-regulated Gene Expression in Human Cells
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依托单位:
Targeting ATDC with PARP inhibitors in pancreatic cancer
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批准号:8061692
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资助金额:$19.33万
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依托单位:
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