CRISPRa induced expression of native MRI reporter proteins
CRISPRa 诱导天然 MRI 报告蛋白的表达
基本信息
- 批准号:10287598
- 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:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAgingBCAR1 geneBinding ProteinsCRISPR therapeuticsCRISPR/Cas technologyCell LineageCell Surface ReceptorsCell SurvivalCell TherapyCell TransplantationCellsChemicalsChromatinChronicClustered Regularly Interspaced Short Palindromic RepeatsColorectal CancerContrast MediaDNA MethylationDetectionDiseaseEngineeringEpigenetic ProcessFDA approvedGene ExpressionGenesGenomeGuide RNAHCT116 CellsHepaticHumanHuman Cell LineImageIn VitroInsertional MutagenesisInvestmentsLeadLinkLiverMagnetic Resonance ImagingMalignant NeoplasmsMediatingMetabolic DiseasesMetalsMethodsModificationMolecular AbnormalityMonitorMusNude MiceOATP TransportersPatientsPentetic AcidPerformancePromoter RegionsProteinsRNA EditingReporterReporter GenesReproducibilityRibonucleoproteinsSignal TransductionSiteSpecificityStretchingSystemTechnologyTestingTherapeuticTimeTissuesToxic effectTranscription Initiation SiteTranscriptional ActivationTranscriptional Activation DomainTranscriptional RegulationTransfectionTransplantationValidationbasecancer cellcell growthcell typeepigenetic regulationexperimental studygene therapygenome editingimaging modalityimmunogenicityin vivoin vivo imaginginduced pluripotent stem cellmRNA Expressionnovel strategiesnovel therapeuticspost-transplantprogramsprotein activationprotein expressionprotein functionquadriceps musclesharing platformtissue regenerationtooltumor
项目摘要
Abstract: Genome editing technologies such as CRISPR-Cas encompass new therapeutic tools for treating and
curing a broad set of diseases ranging from cancer to genetic abnormalities to metabolic diseases, even
stretching as far as combating aging and regenerating tissue. Extending beyond permanent genome
modification, the expanding ensemble of CRISPR technologies based on engineered Cas proteins now possess
capabilities for programmable epigenetic regulation, transcriptional control of native genes, and RNA editing;
moreover, these systems can be combined for orthogonal control of gene expression. These technologies open
up unlimited therapeutic applications but the critical requirement that the targeted or transplanted cells be
monitored and tracked in vivo for verifying both intended and unintended consequences, is unmet.
Here we propose a new paradigm in imaging reporters based on CRISPR-Cas, well suited for in vivo
imaging of cell and gene therapies. Rather than introduce exogenous imaging reporter genes into the genome
or cell, we hypothesize that cell and gene therapies can be imaged in vivo by using CRISPR-mediated
transcriptional activation (CRISPRa) technology to induce expression of native proteins that function as
imaging reporters. We call this paradigm CRISPRa-MRI. The benefits of CRISPRa-MRI are that these
proteins would be inherently human, would only be transiently expressed without disrupting the genome and
would enable multiplexing either with other reporter proteins or CRISPR therapeutics, simultaneously. As a proof-
of-concept, we will focus on the hepatic organic anion transporting polypeptides (OATPs) mouse OATP1A1
(mOATP1A1) and human OATP1B3 (hOATP1B3), recognizing that many other transporters, metal binding
proteins and cell surface receptors are also viable endogenous reporter candidates. mOATP1A1 and hOATP1B3
both specifically transport the FDA-approved MRI contrast agent Gd-EOB-DTPA into cells, the accumulation of
which results in robust bright MRI signal. Normally, expression of these transporters is limited to the liver, but by
using CRISPRa these silent imaging reporter genes can be ‘turned on’ and used to image any cell type or
lineage. CRISPRa-MRI can co-opt the technology used for CRISPR editing or therapeutics in the engineered
cells or gene therapy, avoiding the potential for insertional mutagenesis or chronic expression of an exogenous
gene which may lead to immunogenicity or toxicity, while at the same time eliminating the additional challenge
of delivery and expression of conventional reporter genes. Here we propose to develop a CRISPRa strategy for
activating endogenous mOATP1A1 and hOATP1B3 in vitro (Specific Aim 1) and then test its performance for
in vivo imaging of directly targeted tissues or CRISPRa induction in cells post-transplantation (Specific Aim 2).
The promise of imaging reporter genes for cell and gene-based therapies in humans is, as yet, largely
unfulfilled. CRISPRa-MRI is a completely novel strategy that can help achieve the potential of imaging reporter
genes in humans, especially for monitoring therapies based on CRISPR gene editing or epigenetic modulation.
摘要:CRISPR-Cas等基因组编辑技术为治疗和治疗疾病提供了新的治疗工具
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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Erik Shapiro其他文献
Erik Shapiro的其他文献
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{{ truncateString('Erik Shapiro', 18)}}的其他基金
Evaluation of tantalum oxide nanoparticles for in vivo X-ray computed tomography evaluation of implantable biomaterials
氧化钽纳米颗粒用于植入式生物材料体内 X 射线计算机断层扫描评估的评估
- 批准号:
10326392 - 财政年份:2021
- 资助金额:
$ 22.3万 - 项目类别:
CRISPRa induced expression of native MRI reporter proteins
CRISPRa 诱导天然 MRI 报告蛋白的表达
- 批准号:
10482409 - 财政年份:2021
- 资助金额:
$ 22.3万 - 项目类别:
Evaluation of tantalum oxide nanoparticles for in vivo X-ray computed tomography evaluation of implantable biomaterials
氧化钽纳米颗粒用于植入式生物材料体内 X 射线计算机断层扫描评估的评估
- 批准号:
10548861 - 财政年份:2021
- 资助金额:
$ 22.3万 - 项目类别:
Quantitative molecular and cellular MRI of hepatocyte transplantation
肝细胞移植的定量分子和细胞MRI
- 批准号:
9006872 - 财政年份:2015
- 资助金额:
$ 22.3万 - 项目类别:
Quantitative molecular and cellular MRI of hepatocyte transplantation
肝细胞移植的定量分子和细胞MRI
- 批准号:
9528581 - 财政年份:2015
- 资助金额:
$ 22.3万 - 项目类别:
Quantitative molecular and cellular MRI of hepatocyte transplantation
肝细胞移植的定量分子和细胞MRI
- 批准号:
9313889 - 财政年份:2015
- 资助金额:
$ 22.3万 - 项目类别:
Quantitative molecular and cellular MRI of hepatocyte transplantation
肝细胞移植的定量分子和细胞MRI
- 批准号:
9147584 - 财政年份:2015
- 资助金额:
$ 22.3万 - 项目类别:
(PQC5) MRI of magnetically labeled immune/stem cells for early tumor detection
(PQC5) 磁性标记免疫/干细胞的 MRI 用于早期肿瘤检测
- 批准号:
8686986 - 财政年份:2014
- 资助金额:
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MRI Contrast Agents for In vivo Monitoring of Stem Cell Differentiation
用于干细胞分化体内监测的 MRI 造影剂
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8858631 - 财政年份:2014
- 资助金额:
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MRI Contrast Agents for In vivo Monitoring of Stem Cell Differentiation
用于干细胞分化体内监测的 MRI 造影剂
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8768980 - 财政年份:2014
- 资助金额:
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