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

• 批准号: 10305913
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305913
• 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; Lead; 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/antagonist; 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; skills; stem cell model; stemness; therapeutic target; therapeutically effective; tool; treatment effect; treatment response; tumor; tumor metabolism

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.

项目摘要/摘要 该项目的总体目标是获得必要的技能，以启动具有竞争力的 在生物医学工程领域的独立研究生涯，明确的专长是 癌症新陈代谢研究。癌细胞的异常代谢特征，现在被认为是 癌症的特征，可以是新的诊断生物标志物或治疗靶点。不幸的是， 对癌症新陈代谢的了解仍然有限，这主要是由于缺乏工具。我的龙- 学期的职业目标是领导一个有竞争力的研究团队，主要研究兴趣是开发 允许对癌症新陈代谢进行敏感和高通量分析的新技术。我有过 具有开发灵敏分析平台的丰富经验，具有电子行业背景 工程学。除了我的工程专业知识，来自国际公认的导师 在K99培训期间，癌症生物学方面的专家将对我的职业生涯有所帮助 目标。在目前的研究中，我计划开发一种新的磁传感技术来 全面分析白血病干细胞(LSCs)的代谢，以及获得更深层次的 对癌症生物学的理解。研究计划建立在超极化的发展之上 微核磁共振(HP Micro-核磁共振)技术，使定量分析 两分钟内少量细胞(低至104个细胞)的代谢流量，同时维持更多 超过90%的细胞存活率。重要的是，我开发的新平台允许下游分子 在同一样品中同时进行分析，这可能真正有利于研究质量限制 样本。在这里，我将进一步改进这个系统，以实现更高的灵敏度和增强的分析能力 用于全面分析LSC代谢的吞吐量(目标1)，我将开发HP代谢 用来识别LSCs对代谢酶PHGDH依赖性的标记，它已经成为一种 其他癌症有希望的治疗靶点(目标2)。当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，但必须得到NIH的资助 获得独立奖的途径-母公司K99/R00，拟议的平台将进一步扩展 并在其他临床相关的癌症模型上有广泛的适用性，如患者的活检或肿瘤 有机化合物。