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.

项目摘要/摘要该项目的总体目标是获得发起竞争性，在生物医学工程领域的独立研究职业，具有明确的专业化癌症代谢研究。癌细胞中的异常代谢特征，现在被认为是其中之一癌症的标志可以是新型的诊断生物标志物或治疗靶标。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。我的长期任期职业目标是领导一个具有竞争性研究小组，并具有主要研究兴趣允许对癌症代谢的敏感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的丰富经验工程。除了我的工程专业知识外，国际认可的指导 K99培训期间癌症生物学专家将对我的职业发挥作用目标。在当前的研究中，我计划开发一种新颖的磁传感技术白血病细胞（LSC）中代谢的全面分析，并获得更深的了解癌症生物学。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，可以定量分析在两分钟内，少数细胞（降至104个单元）中的代谢通量，同时保持更多比90％的细胞生存能力。重要的是，我开发的新型平台允许下游分子同一样本中的分析，这可能是对质量限制的真正有益的样品。在这里，我将进一步推进该系统以达到更高的灵敏度和增强的分析性 LSC代谢的综合分析（AIM 1），我将发展HP代谢标记以识别LSC对代谢酶，PHGDH的依赖性，该酶已作为一个其他癌症的有希望的治疗靶标（AIM 2）。当前研究的重点集中在对相关白血病干细胞模型的关键临床需求，但有NIH的命令资金独立之路 - 父母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（例如患者活检或肿瘤）上具有广泛的适用性器官。