Intracellular oxygen sensing using 19F MRI
使用 19F MRI 进行细胞内氧传感
基本信息
- 批准号:8562847
- 负责人:
- 金额:$ 35.08万
- 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:2013-09-01 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:Anti-Inflammatory AgentsAnti-inflammatoryAntigensApoptosisApoptoticBedsBindingBiologicalBiological AssayCD8B1 geneCancer ModelCell CommunicationCell CountCell SurvivalCell TherapyCellsCentral Nervous System NeoplasmsClinicalCytometryCytotoxic T-LymphocytesDataDendritic CellsDevelopmentDrug FormulationsEmployee StrikesEmulsionsEventFluorineFluorocarbonsFoundationsFutureGliomaGoalsHSV-Tk GeneHome environmentHumanImageImageryImmunosuppressionImmunotherapyImplantIn SituInflammationInflammatoryInflammatory Bowel DiseasesInfusion proceduresIntravenous infusion proceduresLabelLeukocytesMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMalignant NeoplasmsMeasurementMeasuresMetabolismMethodsModelingMonitorMusNeuraxisOxygenOxygen saturation measurementPartial PressurePatientsPharmaceutical PreparationsProcessProdrugsPropertyProtocols documentationReagentRelaxationReportingResearch PersonnelRodentSignal TransductionSiteStem cellsSuicide Gene TherapySymptomsT-LymphocyteTechniquesTechnologyTestingTherapeuticTherapy Clinical TrialsThymidine KinaseTimeTissuesTranslationsUniversitiesWorkbasecancer cellcancer therapycell killingcell typechemotherapeutic agentchemotherapydesignimage processingimaging probeimplantationin vivointerestintravenous injectionmacrophagemonocytenanoparticleneoplastic cellnew technologynon-drugpreclinical evaluationpublic health relevancereceptorresearch studyresponsesuicide genetissue culturetooltumoruptake
项目摘要
DESCRIPTION (provided by applicant): A widely recognized limitation of MRI cell tracking using nanoparticle probes is that they cannot report on cellular activity or cell viability in vivo Non-invasive cell tracking methods that can monitor changes in cell viability and activation would be a great value in the development of cancer treatments, cell therapies, and anti-inflammatory drugs. Towards these goals, we will explore the utility of real-time monitoring of intracellular oximetry in vivo using perfluorocarbon (PFC) emulsion imaging probes. This proposal builds on our prior work developing MRI cell tracking methods for ex vivo and in situ labeling of cells with PFC imaging reagents. For ex vivo cell labeling, isolated cells of interest (e.g., leukocytes, stem cells, or cancer cells) are labeled in culture with PFC emulsion, and following transfer to the subject, cells are tracked in vivo using fluorine-19 (19F) MRI. The fluorine signal yields cell-specific images, with no background, that can be used to quantify apparent cell numbers at sites of accumulation. For in situ labeling, PFC emulsion is injected intravenously and taken up by macrophages that home to sites of inflammation and can be visualized by 19F MRI. In this proposal, we will exploit the oxygen sensing properties of the intracellular PFC molecules. Oxygen binding to PFC results in a reduction in the 19F spin-lattice relaxation time (T1), where T1 varies linearly with the partial pressure of oxygen (pO2). Hence, we propose combining 19F-based cell tracking with 19F T1 measurements to monitor intracellular pO2 in a cell-specific manner. Results from our lab in cancer models have demonstrated the feasibility of measuring the absolute intracellular pO2 in tumor cells and response to anti-cancer treatments. Overall, the proposal has two Specific Aims. Aim 1: Can intracellular pO2 detect cell viability in vivo? We will test the hypothesis that a measureable increase in pO2 is an indirect consequence of apoptotic processes. In tumor cells, we will characterize the cellular pO2 response following chemotherapy, suicide gene therapy, and effector T cell immunotherapy, all of which drive the cell towards apoptosis, but employ different triggers. The establishment of a relationship between cell viability and intracellular pO2 can be exploited in the preclinical evaluation of emerging cancer therapies. Moreover, as human clinical translation of 19F cell tracking matures, these oximetry techniques may be used in cell therapy clinical trials to determine whether the cellular graft is viable after delivery to the patient. Stdies in tumor models will help set the foundation for future studies in a variety of therapeutic cell types. Aim 2: Can macrophage intracellular pO2 detect immunoactivity? In a further extension, we will test the hypothesis that macrophages localized at sites of inflammation will respond to pharmacological immunosuppression by altering intracellular pO2 levels. A murine model of inflammatory bowel disease will be used, along with in situ PFC labeling of macrophages. We will test whether macrophage intracellular pO2 can be used as a tool to assess anti-inflammatory drugs non-invasively. Overall, the proposed experiments will set the foundation for a broad field of inquiries using intracellular PFC cell tracking agents to garner information about
real-time cell metabolism in vivo.
描述(由申请人提供):使用纳米颗粒探针的MRI细胞跟踪的一个广泛认识到的局限性是它们不能报告体内细胞活性或细胞活力。可以监测细胞活力和活化变化的非侵入性细胞跟踪方法在癌症治疗、细胞疗法和抗炎药物的开发中将具有很大的价值。为了实现这些目标,我们将探讨使用全氟化碳(PFC)乳剂成像探针在体内实时监测细胞内血氧饱和度的实用性。该建议建立在我们先前的工作开发MRI细胞跟踪方法的体外和原位标记的细胞与PFC成像试剂。对于离体细胞标记,分离的感兴趣的细胞(例如,白细胞、干细胞或癌细胞)在培养物中用PFC乳液标记,并在转移到受试者后,使用氟-19(19 F)MRI在体内追踪细胞。氟信号产生细胞特异性图像,没有背景,可用于量化积累部位的表观细胞数量。对于原位标记,PFC乳剂经静脉注射并被巨噬细胞摄取,巨噬细胞归巢至炎症部位并可通过19 F MRI可视化。在这个提议中,我们将利用细胞内PFC分子的氧传感特性。氧与PFC结合导致19 F自旋晶格弛豫时间(T1)减少,其中T1随氧分压(pO 2)线性变化。因此,我们建议将基于19 F的细胞跟踪与19 F T1测量相结合,以细胞特异性方式监测细胞内pO 2。我们实验室在癌症模型中的结果证明了测量肿瘤细胞中绝对细胞内pO 2和对抗癌治疗反应的可行性。总的来说,该提案有两个具体目标。目的1:细胞内pO 2能否检测体内细胞活力?我们将检验这一假设,即pO 2的可测量增加是凋亡过程的间接结果。在肿瘤细胞中,我们将描述化疗,自杀基因治疗和效应T细胞免疫治疗后的细胞pO 2反应,所有这些都驱动细胞凋亡,但采用不同的触发器。细胞活力和细胞内pO 2之间关系的建立可用于新兴癌症疗法的临床前评价。此外,随着19 F细胞追踪的人类临床翻译的成熟,这些血氧测定技术可用于细胞治疗临床试验中,以确定细胞移植物在递送给患者后是否有活力。肿瘤模型的研究将有助于为各种治疗细胞类型的未来研究奠定基础。目的2:巨噬细胞内pO 2是否能检测免疫活性?在进一步的扩展中,我们将测试这样的假设:位于炎症部位的巨噬细胞将通过改变细胞内pO 2水平来对药理学免疫抑制做出反应。将使用炎症性肠病的小鼠模型,沿着巨噬细胞的原位PFC标记。我们将测试巨噬细胞内pO 2是否可以用作非侵入性评估抗炎药物的工具。总的来说,拟议的实验将为使用细胞内PFC细胞追踪剂来收集以下信息的广泛领域奠定基础:
体内实时细胞代谢。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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ERIC T. AHRENS其他文献
ERIC T. AHRENS的其他文献
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Intracellular oxygen sensing using 19F MRI
使用 19F MRI 进行细胞内氧传感
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