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Dual-modal Microscopy of Metabolic Reprogramming in Cancer

癌症代谢重编程的双模式显微镜

基本信息

批准号：
9187011
负责人：
Song Hu
金额：
$ 18.57万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187011
关键词：
Acoustics Adverse effects Alzheimer&apos s Disease Bioenergetics Biological Markers Blood Blood flow Cancer Detection Cancerous Characteristics Coenzymes Communities Custom Darkness Detection Development Diabetes Mellitus Disease Ear Evolution Flavin-Adenine Dinucleotide Foundations Frequencies Genetic Glucose Glycolysis Gold Grant Hand Hemoglobin Image In Vitro Label Lasers Length MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolism Microscope Microscopic Microscopy Mitochondria Modality Modeling Monitor Mus Nicotinamide adenine dinucleotide Normal tissue morphology Obesity Oncogenic Optics Oxidation-Reduction Oxidative Phosphorylation Oxides Oxygen Pancreas Pathogenicity Performance Principal Investigator Process Research Research Personnel Resolution Role Scanning Screening for cancer Signal Transduction Structure System Techniques Technology Testing Time Tissues Transducers Ultrasonic Transducer Xenograft Model base data acquisition design driving force effective therapy fluorescence lifetime imaging follow-up high resolution imaging in vivo indexing innovation insight meetings metabolic imaging metabolic phenotype metabolic rate mitochondrial dysfunction mouse model new therapeutic target novel performance tests prototype public health relevance spatiotemporal targeted treatment tumor tumor initiation tumor metabolism tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Metabolic reprogramming, the shift from oxidative to glycolytic metabolism, has been increasingly considered as a core hallmark of cancer. Our recent in vitro study suggests that metabolic reprogramming may be the underlying mechanism through which oncogenic Ras-induced mitochondrial dysfunction drives tumor initiation and progression. Examining this innovative and important hypothesis holds great promise to advance our understanding of the metabolic signaling in cancer and inspire new strategies for early cancer detection and targeted therapy. However, it has been impeded by the lack of a technology capable of dynamically imaging the metabolic shift at the microscopic level in vivo. The proposed research aims to meet this stringent demand by developing a reflection-mode dual-modal microscopy platform. Integrating two cutting-edge techniques- photoacoustic microscopy (PAM) and multiphoton fluorescence lifetime imaging microscopy (MPFLIM)-in a radically new way, this platform will enable concurrent imaging of two gold-standard metabolic indices: the metabolic rate of oxygen (MRO2) and optical redox ratio. Co-evolution of the two indices will quantitatively and dynamically delineate metabolic reprogramming during cancer development. To this end, we have organized this project around three specific aims. First, we will develop an optical-acoustic objective by integrating a high- frequency ultrasonic transducer and a reflective microscope objective. This novel design will enable the natural integration of optical excitation (for both PAM and MPFLIM) and acoustic detection (for PAM only) in reflection mode. Then, we will implement the dual-modal microscopy platform based on our existing MPFLIM system. Concurrent detection of optically-absorbing blood hemoglobin and autofluorescent metabolic coenzymes (i.e., NADH and FAD) through properly designed dual-modal scan and data acquisition will enable, for the first time, in vivo high-resolution imaging of MRO2 and optical redox ratio at the same spatiotemporal scale. Ultimately, validating the performance of the platform in a mouse tumor model will prepare us for follow-up mechanistic studies of the role of Ras-induced mitochondrial dysfunction in metabolic reprogramming and tumorigenesis. Successful completion of this developmental grant will lead to a technical breakthrough in the field of metabolic imaging and allow us to tackle important questions, including whether genetic inhibition of mitochondrial fission can reverse metabolism reprogramming and which genetic factors contribute to the metabolic phenotypes in cancer. These studies not only will give us a clearer understanding of cancer metabolic signaling but also may identify new therapeutic targets for the treatment of Ras-driven malignancies. The potential impact of the dual- modal microscopy could be very broad, because metabolic reprogramming contributes to the development of numerous diseases besides cancers, including but not limited to Alzheimer disease, obesity, and diabetes. The robust performance and ease of implementation, enabled by the novel optical-acoustic objective, will pave the way for disseminating this promising technique throughout the research community.

描述（由申请人提供）：代谢重编程，即从氧化代谢到糖酵解代谢的转变，已越来越多地被认为是癌症的核心标志。我们最近的体外研究表明，代谢重编程可能是致癌Ras诱导的线粒体功能障碍驱动肿瘤发生和进展的潜在机制。研究这一创新和重要的假设，对于推进我们对癌症代谢信号的理解，并激发早期癌症检测和靶向治疗的新策略，具有很大的希望。然而，由于缺乏能够在体内微观水平上动态成像代谢转变的技术，这一研究受到了阻碍。拟议的研究旨在通过开发反射模式双模显微镜平台来满足这一严格的需求。该平台以全新的方式集成了两种尖端技术-光声显微镜（PAM）和多光子荧光寿命成像显微镜（MPFLIM），将能够同时成像两个金标准代谢指标：氧代谢率（MRO 2）和光学氧化还原比。这两个指标的共同演变将定量和动态地描绘癌症发展过程中的代谢重编程。为此，我们围绕三个具体目标组织了这个项目。首先，我们将发展一个整合高频超音波换能器与反射式显微镜物镜的光声物镜。这种新颖的设计将使得能够在反射模式中自然地集成光学激发（对于PAM和MPFLIM两者）和声学检测（仅对于PAM）。然后，我们将实现基于我们现有的MPFLIM系统的双模显微镜平台。同时检测光吸收血液血红蛋白和自发荧光代谢辅酶（即，NADH和FAD）通过适当设计的双模式扫描和数据采集将首次实现体内高分辨率成像， MRO 2和光学氧化还原比在同一时空尺度。最终，在小鼠肿瘤模型中验证该平台的性能将为我们对Ras诱导的线粒体功能障碍在代谢重编程和肿瘤发生中的作用的后续机制研究做好准备。成功完成这项发展资助将导致代谢成像领域的技术突破，并使我们能够解决重要问题，包括线粒体裂变的遗传抑制是否可以逆转代谢重编程以及哪些遗传因素有助于癌症的代谢表型。这些研究不仅将使我们更清楚地了解癌症代谢信号，还可能为Ras驱动的恶性肿瘤的治疗确定新的治疗靶点。双模式显微镜的潜在影响可能非常广泛，因为代谢重编程有助于癌症以外的许多疾病的发展，包括但不限于阿尔茨海默病、肥胖症和糖尿病。强大的性能和易于实施，使新的光声目标，将铺平道路，传播这种有前途的技术在整个研究界。