Extracellular Vesicle-Based Digital Scoring Assay for Detecting Early-stage Hepatocellular Carcinoma
基于细胞外囊泡的数字评分法检测早期肝细胞癌
基本信息
- 批准号:10560611
- 负责人:
- 金额:$ 63.28万
- 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:2021-01-18 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AFP geneAbdomenAddressAlcoholic Liver DiseasesAntibodiesBioinformaticsBiologicalBiological AssayBiological MarkersBiologyBiometryCancer EtiologyCessation of lifeChemistryCirculationCirrhosisClinicalCouplesDevelopmentDevicesDiagnosisDiagnosticDisulfidesEarly DiagnosisEnsureEtiologyEvaluationExhibitsFiltrationGoalsHepatitis BHepatitis CImageInfectionJointsLiverLiver CirrhosisMediatingMedical centerMessenger RNAMethodsMicrofluidicsMinorModalityModelingMotivationNanostructuresNon-Invasive DetectionOncologyOperative Surgical ProceduresPatientsPerformancePhospholipidsPlasmaPopulationPrecipitationPrimary carcinoma of the liver cellsQuantitative EvaluationsRegimenReportingReproducibilityResearchResearch PersonnelReverse TranscriptionRiskRisk FactorsSamplingSecondary toSensitivity and SpecificitySerumSiteSolid NeoplasmSpecific qualifier valueSpecificitySpecimenSurfaceTechniquesTechnologyTrainingTumor-DerivedUltracentrifugationUltrasonographyValidationassay developmentcell typecohortdetection assaydiagnostic valuedigitalextracellular vesicleshepatocellular carcinoma cell linein-vitro diagnosticsinnovationmolecular pathologynanomaterialsneoplastic cellnon-alcoholic fatty liver diseaseparticlestandard of caretumor heterogeneityvesicular release
项目摘要
PROJECT SUMMARY
Extracellular vesicles (EVs) are a heterogeneous group of phospholipid bilayer-enclosed particles that are
released by all types of cells, and even more so by tumor cells. Since the biomolecular cargoes of tumor-
derived EVs mirror those of the parental tumor cells, characterizing tumor-derived EVs and profiling their cargo
are expected to be of substantial diagnostic value. Hepatocellular carcinoma (HCC), the fourth most common
cause of cancer-related deaths worldwide, most often develops in patients with underlying liver cirrhosis
secondary to alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), or hepatitis B/C
infections. Cirrhosis from any cause is a well-established risk factor for HCC; however, current surveillance
regimens with abdominal imaging and serum biomarkers (e.g., AFP) have poor sensitivity for diagnosing HCC
at an early stage, when it is potentially curable. Therefore, biomarkers that sensitively distinguish early-stage
HCC from at-risk liver cirrhosis are desperately needed. Exploring the diagnostic potential of HCC EVs and EV
cargo profiling for detecting early-stage HCC holds great promise to significantly augment the ability of current
diagnostic modalities.
We propose an HCC EV digital scoring assay for detecting early-stage HCC, which couples two very powerful
technologies: EV Click Chip for purification of HCC EVs and reverse-transcription droplet digital PCR (RT-
ddPCR) for EV cargo profiling. One of the major challenges emerging in the field of EV utilization for clinical
use is the lack of robust and reproducible methods for the isolation of a pure tumor-derived EV population.
Conventional methods for isolating EVs, such as ultracentrifugation, filtration, and precipitation, are incapable
of discriminating tumor-derived EVs from non-tumor-derived EVs. New research efforts have been devoted to
exploring immunoaffinity-based capture techniques for enriching tumor-derived EVs in different solid tumors.
However, there are challenges identified for the single antibody-mediated tumor-derived EV enriching
approaches, such as limited sensitivity/specificity and a need for multiple capture antibodies to overcome the
tumor heterogeneity. The EV Click Chips can address these concerns with a 2-step covalent chemistry-based
tumor-derived EV purification (click chemistry-mediated EV capture/disulfide cleavage-driven EV release)
instead of antibody-mediated EV capture. The purified HCC EVs can then be characterized by quantifying a
panel of 20 HCC-specific mRNA markers by incorporating RT-ddPCR technology. The proposed research will
conduct: i) an exploratory development and optimization of the two functional components (i.e., EV Click Chip
and RT-ddPCR) and analytically validate the proposed HCC EV digital scoring assay, and ii) an evaluation of
the diagnostic performance of the proposed HCC EV digital scoring assay for detecting early-stage HCC using
training and validation cohorts. The long-term goal of this R01 proposal is to develop, optimize, and validate
the proposed HCC EV digital scoring assay for detecting early-stage HCC from at-risk liver cirrhotic patients.
项目摘要
细胞外囊泡(EV)是一组异质的磷脂双层封闭的颗粒,
所有类型的细胞都会释放,肿瘤细胞更是如此。因为肿瘤的生物分子-
衍生的EV反映了亲本肿瘤细胞的EV,表征了肿瘤衍生的EV并分析了它们的货物
预计将具有重要的诊断价值。肝细胞癌(HCC),第四常见的
是全球范围内癌症相关死亡的原因,最常发生在基础肝硬化患者中
继发于酒精性肝病(ALD)、非酒精性脂肪性肝病(NAFLD)或B/C型肝炎
感染.任何原因引起的肝硬化都是HCC的一个公认的危险因素;然而,目前的监测
具有腹部成像和血清生物标记物的方案(例如,AFP)诊断HCC的敏感性差
在早期阶段,当它是有可能治愈的。因此,敏感区分早期阶段的生物标志物
迫切需要高危肝硬化的HCC。探索HCC EV和EV的诊断潜力
用于检测早期HCC的货物分析具有很大的希望,可以显著提高目前的检测能力。
诊断模式。
我们提出了一种用于检测早期HCC的HCC EV数字评分测定法,其将两种非常强大的
技术:用于纯化HCC EV的EV点击芯片和逆转录液滴数字PCR(RT-PCR)。
ddPCR)用于EV货物分析。EV临床应用领域出现的主要挑战之一是
使用的是缺乏用于分离纯肿瘤衍生EV群体的稳健和可重复的方法。
用于分离EV的常规方法,例如超离心、过滤和沉淀,不能用于分离EV。
区分肿瘤来源的EV和非肿瘤来源的EV的能力。新的研究工作致力于
探索基于免疫亲和性的捕获技术,用于富集不同实体瘤中的肿瘤衍生EV。
然而,对于单抗体介导的肿瘤来源的EV富集存在挑战,
方法,如有限的灵敏度/特异性和需要多种捕获抗体来克服
肿瘤异质性EV点击芯片可以通过基于两步共价化学的
肿瘤衍生的EV纯化(点击化学介导的EV捕获/二硫键裂解驱动的EV释放)
而不是抗体介导EV捕获。纯化的HCC EV然后可以通过定量HCC EV的浓度来表征。
一组20种HCC特异性mRNA标记物,通过结合RT-ddPCR技术。拟议的研究将
进行:i)两个功能组件的探索性开发和优化(即,EV Click芯片
和RT-ddPCR)并分析验证所提出的HCC EV数字评分测定,和ii)评估
所提出的HCC EV数字评分测定用于检测早期HCC的诊断性能,
培训和验证队列。本R01提案的长期目标是开发、优化和验证
提出的HCC EV数字评分测定用于从高危肝硬化患者中检测早期HCC。
项目成果
期刊论文数量(0)
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{{ truncateString('Yazhen Zhu', 18)}}的其他基金
Extracellular Vesicle-Based Digital Scoring Assay for Detecting Early-stage Hepatocellular Carcinoma
基于细胞外囊泡的数字评分法检测早期肝细胞癌
- 批准号:
10097789 - 财政年份:2021
- 资助金额:
$ 63.28万 - 项目类别:
Extracellular Vesicle-Based Digital Scoring Assay for Detecting Early-stage Hepatocellular Carcinoma
基于细胞外囊泡的数字评分法检测早期肝细胞癌
- 批准号:
10330444 - 财政年份:2021
- 资助金额:
$ 63.28万 - 项目类别:
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