Defining Strategies to Target Energy Failure in Metabolically Vulnerable Human Cells

制定针对代谢脆弱的人体细胞能量衰竭的策略

基本信息

批准号：
10237384
负责人：
KEN NAKAMURA
金额：
$ 64.58万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10237384
关键词：
Address Aging Bioenergetics Biological Assay Biosensor CRISPR interference Cardiac Myocytes Cell Line Cell physiology Cells Cessation of life Consumption Disease Energy Metabolism Failure Fluorescence Resonance Energy Transfer Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Genes Genetic Genetic Epistasis Genetic Transcription Glycolysis Goals Heart Diseases Heart failure Human Individual Ischemia K562 Cells Lead Leukemic Cell Libraries Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolic Mitochondria Neurodegenerative Disorders Neurons Oxygen Pathway interactions Production Respiration Respiratory physiology Role Synapses Testing Therapeutic anti aging base cell type deprivation experimental study high throughput screening hypoxia inducible factor 1 improved innovation metabolomics preservation protective effect respiratory sensor transcriptomics whole genome

项目摘要

Project Summary Disrupted energy metabolism is a central driver of dysfunction and death in a wide range of diseases, and may also contribute to aging. Energy failure, or insufficient energy to support normal function, can lead to neurodegenerative diseases, ischemia and heart failure, while an imbalance in energy production may contribute to cancer. As such, boosting energy levels has great therapeutic potential to improve cellular function and survival. However, there are only anecdotal examples of how to increase or preserve cellular ATP levels. To address this critical unmet need for anti-aging and energy-focused therapeutics, we developed an innovative high throughput screen that uses a fluorescent biosensor to measure ATP levels in individual cells, and used it to identify genes and pathways that regulate ATP levels. In this proposal, we will test our central hypothesis that increasing ATP can enhance the function and survival of vulnerable cells, but the efficacy depends on the mechanism by which ATP is increased. The overall objectives of our proposed study are to define the most robust mechanisms to increase cellular energy levels, and to determine if increasing ATP boosts the function and survival of human cells that are susceptible to diseases of energy failure. We will accomplish these objectives in two specific aims. (1) We will use metabolomics, transcriptomics and assays of energy production and consumption to determine the broad mechanisms by which energy levels can be increased. (2) We will determine if increasing the ATP level can enhance the function and survival of human neurons and cardiomyocytes. Overall, these studies will i) determine the broad cellular mechanisms by which cellular energy levels can be increased, and ii) begin to assess the therapeutic potential of increasing energy levels to protect against energy failure in metabolically vulnerable human cells.

项目概要能量代谢紊乱是多种疾病功能障碍和死亡的核心驱动因素，并且可能也有助于衰老。能量衰竭或能量不足以支持正常功能，可能会导致神经退行性疾病、缺血和心力衰竭，而能量产生的不平衡可能会导致到癌症。因此，提高能量水平对于改善细胞功能和治疗具有巨大的治疗潜力。生存。然而，关于如何增加或保持细胞 ATP 水平，只有轶事例子。到为了解决抗衰老和能量集中疗法这一未满足的关键需求，我们开发了一种创新的高通量筛选，使用荧光生物传感器测量单个细胞中的 ATP 水平，并使用它识别调节 ATP 水平的基因和途径。在这个提案中，我们将测试我们的中心假设增加 ATP 可以增强脆弱细胞的功能和生存，但功效取决于 ATP增加的机制。我们提出的研究的总体目标是定义最增加细胞能量水平的强大机制，并确定增加 ATP 是否会增强功能以及易患能量衰竭疾病的人类细胞的生存。我们将实现这些目标有两个具体目标。 (1) 我们将使用代谢组学、转录组学和能量产生和分析方法来确定提高能量水平的广泛机制。 (2) 我们将确定如果增加ATP水平可以增强人类神经元和心肌细胞的功能和存活。全面的，这些研究将 i) 确定可以提高细胞能量水平的广泛细胞机制， ii) 开始评估增加能量水平的治疗潜力，以防止能量衰竭代谢脆弱的人体细胞。