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Hyperpolarized Micro-NMR for Quantitative Analysis of Metabolism in Leukemia Stem Cells

用于白血病干细胞代谢定量分析的超极化微核磁共振

基本信息

批准号：
10544545
负责人：
Sangmoo Jeong
金额：
$ 24.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544545
关键词：
Achievement Acute Myelocytic Leukemia Address Award Benchmarking Biochemical Reaction Biomedical Engineering Biopsy Bone Marrow Cells Cancer Biology Cancer Model Cell Survival Cells Cellular Metabolic Process Clinical Data Dependence Detection Development Disease Disease model Electrical Engineering Engineering Enzymes Experimental Designs Funding Gatekeeping Genetic Goals Hematopoietic In Vitro International Label Leukemic Cell Magnetism Malignant Neoplasms Mass Spectrum Analysis Mentors Mentorship Metabolic Metabolic Marker Metabolic Pathway Metabolism Microfluidics Microscopy Miniaturization Molecular Analysis Monitor Mus Nuclear Magnetic Resonance Optics Organoids Outcome Oxidation-Reduction Parents Pathway interactions Patients Pharmacotherapy Phase Preparation Pyruvate Reaction Recurrence Relaxation Research Resistance Sampling Serine Signal Transduction System Techniques Technology Testing Therapeutic Time Training United States National Institutes of Health Work acute myeloid leukemia cell advanced system cancer cell cancer stem cell career clinically relevant conventional therapy dehydroascorbate diagnostic biomarker experience experimental analysis high throughput analysis in vivo inhibitor interest knock-down leukemia leukemia initiating cell leukemic stem cell leukemogenesis metabolic abnormality assessment metabolic imaging miniaturize new technology new therapeutic target novel novel diagnostics predictive marker prototype sensor technology skill acquisition stem cell model stemness therapeutic target therapeutically effective tool treatment effect treatment response tumor tumor metabolism

项目摘要

Project Summary/Abstract The overarching goal of this project is to acquire the skills necessary to launch a competitive, independent research career in the field of biomedical engineering, with an explicit specialization in cancer metabolism research. Aberrant metabolic features in cancer cells, now recognized as one of the hallmarks of cancer, can be novel diagnostic biomarkers or therapeutic targets. Unfortunately, understanding of cancer metabolism remains limited, which is primarily due to the lack of tools. My long- term career goal is to lead a competitive research group, with primary research interests in developing novel technologies that allow sensitive and high-throughput analysis of cancer metabolism. I have extensive experience in developing sensitive analytical platforms with a background in electrical engineering. In addition to my engineering expertise, the mentorship from internationally recognized experts in cancer biology during the K99 training period will be instrumental towards my career objectives. In the current research, I plan to develop a novel magnetic sensing technology for comprehensive analysis of metabolism in leukemia stem cells (LSCs), as well as to acquire a deeper understanding of cancer biology. The Research Plan is built upon the development of the hyperpolarized micro nuclear magnetic resonance (HP micro-NMR) technology that enables quantitative analysis of metabolic flux in a small number of cells (down to 104 cells) within two minutes, while maintaining more than 90% of cell viability. The novel platform I developed, importantly, allowed downstream molecular analyses in the same sample in tandem, which may be truly beneficial for investigating mass-limited samples. Here, I will advance this system further to achieve a higher sensitivity and enhanced analytical throughput for comprehensive analysis of LSC metabolism (Aim 1), and I will develop HP metabolic markers to identify the dependence of LSCs on a metabolic enzyme, PHGDH, which has emerged as a promising therapeutic target for other cancers (Aim 2). The focus of the current research is centered on the critical clinical need for relevant leukemia stem cells models, but with imperative funding from the NIH Pathway to Independence Award - Parent K99/R00, the proposed platform would extend much further and have wide applicability on other clinically relevant cancer models, such as patient biopsies or tumor organoids.

项目概要/摘要该项目的总体目标是获得启动有竞争力的、在生物医学工程领域的独立研究生涯，明确的专业是癌症代谢研究。癌细胞中异常的代谢特征，现在被认为是癌症的标志，可以是新的诊断生物标志物或治疗靶点。很遗憾，对癌症代谢的了解仍然有限，这主要是由于缺乏工具。我的长- 学期职业目标是领导一个有竞争力的研究小组，主要研究兴趣是开发允许对癌症代谢进行灵敏和高通量分析的新技术。我有在开发具有电气背景的敏感分析平台方面拥有丰富的经验工程。除了我的工程专业知识之外，还得到国际公认的指导 K99 培训期间的癌症生物学专家将对我的职业生涯发挥重要作用目标。在目前的研究中，我计划开发一种新颖的磁传感技术全面分析白血病干细胞（LSC）的代谢，并获得更深入的了解了解癌症生物学。该研究计划建立在超极化的发展基础上微核磁共振 (HP micro-NMR) 技术可实现对两分钟内少量细胞（低至 104 个细胞）的代谢通量，同时保持更多超过90%的细胞活力。重要的是，我开发的新颖平台允许下游分子对同一样品进行串联分析，这可能真正有利于研究质量限制样品。在这里，我将进一步改进该系统，以实现更高的灵敏度和增强的分析能力综合分析LSC代谢（目标1）的吞吐量，我将开发HP代谢标记来识别 LSC 对代谢酶 PHGDH 的依赖性，PHGDH 已成为一种其他癌症有希望的治疗靶点（目标 2）。目前的研究重点集中在相关白血病干细胞模型的关键临床需求，但需要 NIH 的资助独立之路奖 - 母版 K99/R00，拟议的平台将进一步扩展并在其他临床相关癌症模型上具有广泛的适用性，例如患者活检或肿瘤类器官。