Endothelial Progenitor Cells for Assessing Toxicological Response Variability in Humans
用于评估人类毒理学反应变异性的内皮祖细胞
基本信息
- 批准号:9301840
- 负责人:
- 金额:$ 30.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-15 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlgorithmsAnimal ModelAnimalsAutomationBiological AssayBloodBlood CirculationBlood VesselsBlood specimenCD34 geneCadmiumCell Culture TechniquesCell Cycle ArrestCell DeathCell Differentiation processCell LineCell SeparationCell SurvivalCellsChemicalsCommunitiesContractsCulture MediaDataData SetDetectionDevelopmentDevelopmental ProcessDifferentiation AntigensDonor SelectionDoseEndothelial CellsEnvironmental HealthEvaluationExhibitsExposure toFlow CytometryFutureGlycocalyxGoalsHealthHumanImageIn VitroIndividualIonizing radiationLinkLiquid substanceMaintenanceMediatingMethodsModelingOxidative StressPECAM1 genePathway interactionsPhasePhysiologyPopulationProceduresProductionProteinsReactive Oxygen SpeciesReagentReportingResearchRisk AssessmentScientistServicesSignal TransductionSourceSpecific qualifier valueStem cellsTimeToxic Environmental SubstancesToxic effectToxicant exposureToxicologyToxinTranslatingUmbilical cord structureValidationWestern Blottingbasebisphenol Acadherin 5cell growthcell typecommercializationelectric impedanceenvironmental agentexperiencehigh throughput screeningimaging platformimmortalized cellin vivoin vivo Modelinsightnovelperfluorooctanoic acidperipheral bloodphase 1 studyprogramsrepositoryresponsescreeningtoxicanttoxicant screeningvon Willebrand Factor
项目摘要
DESCRIPTION (provided by applicant): Toxicological risk assessment lacks direct estimation of the magnitude and variability of human responses to environmental toxicants. Specifically, there is very little data on the effects of low dose toxicants on human developmental processes, including cellular differentiation. That is because the current basis of toxicological assessment, animals and immortalized cell lines, cannot adequately model the impact of low level toxicant exposure on human populations. An alternative detection platform should enable incorporation of human variability in screening of a large number of toxicants in a high-throughput manner. To establish such a platform, we propose using human donor-specific cells that can be (a) isolated in a non-invasive manner, (b) easily expanded in culture, and (c) cryopreserved without loss of viability. Our preliminary data suggest that human endothelial progenitor cells, or endothelial colony forming cells (ECFCs), a population of CD31+/CD34+ pluripotent cells found in circulating blood, would fulfill these requirements. ECFCs are highly proliferative in vitro and ca differentiate into mature endothelial cells (ECs). The overall goal of this research is to evaluate
the effect of chemical toxicants on viability, proliferation, and differentiation of ECFCs derived from different individuals. Prior to our recent and successful completion of a Phase I program, we established cell culture parameters for ECFCs using a proprietary cell growth media supplement and completed initial toxicological risk assessment studies using low-dose ionizing radiation (LDIR). These studies confirmed the utility of ECFCs in toxicological risk assessment screening as well as their ability to broadly represent varying responses expected in human populations. Phase I studies successfully expanded these findings by performing ECFC toxicology assays using Bisphenol A (BPA), perfluorooctanoic acid (PFOA) and cadmium (Cd). ECFCs were found to be sensitive to BPA and Cd and less sensitive to PFOA, exhibiting donor-specific variability in proliferation rates. BPA and Cd also induced reactive oxygen species (ROS) production in a donor-specific manner. ECFCs were shown to experience oxidative stress and cell cycle arrest after exposure to toxicants. Elevated ROS production was shown to correlate with cell death after longer incubation times with toxicants. We found that the toxicants
we analyzed also affected expression of endothelial-specific cell markers at a protein level in a newly developed differentiation assay. Phase II will focus on the continued development of this screening platform toward a validated quantitative high content imaging-based screen. Commercialization of the platform as a service will also be pursued as well as the production of kits for ECFC culture and subsequent toxicological analysis. Finally, the screen will be expanded to include toxicant-induced effects on ECFC differentiation into mature endothelial cells.
描述(由申请方提供):毒理学风险评估缺乏对人类对环境毒物反应的程度和变异性的直接估计。具体而言,关于低剂量毒物对人类发育过程(包括细胞分化)影响的数据很少。这是因为目前毒理学评估的基础,动物和永生化细胞系,不能充分模拟低水平毒物暴露对人群的影响。一种替代的检测平台应该能够以高通量的方式在筛选大量毒物时纳入人的变异性。为了建立这样的平台,我们提出使用人供体特异性细胞,其可以(a)以非侵入性方式分离,(B)在培养中容易扩增,和(c)冷冻保存而不丧失活力。我们的初步数据表明,人内皮祖细胞,或内皮集落形成细胞(ECFC),在循环血液中发现的CD 31 +/CD 34+多能细胞群,将满足这些要求。ECFC在体外高度增殖,并且可以分化为成熟的内皮细胞(EC)。本研究的总体目标是评估
化学毒物对来自不同个体的ECFC的活力、增殖和分化的影响。在我们最近成功完成I期项目之前,我们使用专有的细胞生长培养基补充剂建立了ECFC的细胞培养参数,并使用低剂量电离辐射(LIFE)完成了初步毒理学风险评估研究。这些研究证实了ECFC在毒理学风险评估筛选中的实用性,以及它们广泛代表人群中预期的不同反应的能力。I期研究通过使用双酚A(BPA)、全氟辛酸(PFOA)和镉(Cd)进行ECFC毒理学试验,成功地扩展了这些发现。ECFCs被认为是敏感的BPA和镉和不太敏感的PFOA,表现出供体特异性的增殖率的变化。BPA和镉也诱导活性氧(ROS)的生产在一个特定的方式。ECFC暴露于有毒物质后表现出氧化应激和细胞周期停滞。升高的ROS产生被证明与毒物孵育时间较长后的细胞死亡相关。我们发现有毒物质
我们还在新开发的分化测定中在蛋白质水平上分析了内皮特异性细胞标志物的受影响的表达。第二阶段将侧重于继续开发该筛查平台,以实现经验证的定量高内容成像筛查。该平台作为一项服务的商业化也将继续进行,并将生产用于ECFC培养和随后的毒理学分析的试剂盒。最后,筛选将扩大到包括对ECFC分化为成熟内皮细胞的毒性诱导作用。
项目成果
期刊论文数量(0)
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John William Ludlow其他文献
John William Ludlow的其他文献
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{{ truncateString('John William Ludlow', 18)}}的其他基金
Endothelial Progenitor Cells for Assessing Toxicological Response Variability in Humans
用于评估人类毒理学反应变异性的内皮祖细胞
- 批准号:
9149273 - 财政年份:2013
- 资助金额:
$ 30.87万 - 项目类别:
Endothelial Progenitor Cells for Assessing Toxicological Response Variability in Humans
用于评估人类毒理学反应变异性的内皮祖细胞
- 批准号:
9019006 - 财政年份:2013
- 资助金额:
$ 30.87万 - 项目类别:
Endothelial Progenitor Cells for Assessing Toxicological Response Variability in
用于评估毒理学反应变异性的内皮祖细胞
- 批准号:
8620435 - 财政年份:2013
- 资助金额:
$ 30.87万 - 项目类别:
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