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.

项目摘要能源代谢中断是功能障碍和死亡的核心驱动力，并且可能也有助于衰老。能量故障或支持正常功能的能量不足，可能会导致神经退行性疾病，缺血和心力衰竭，而能量产生的失衡可能会导致癌症。因此，提高能量水平具有改善细胞功能的巨大治疗潜力和生存。但是，只有有关如何增加或保留细胞ATP水平的轶事示例。到满足了对抗衰老和以能量为中心的治疗药的关键需求，我们开发了一种创新的高吞吐量屏幕，该屏幕使用荧光生物传感器来测量单个细胞中的ATP水平，并使用了它确定调节ATP水平的基因和途径。在此提案中，我们将检验我们的中心假设增加的ATP可以增强脆弱细胞的功能和存活，但功效取决于 ATP增加的机制。我们拟议的研究的总体目标是定义最大的目标强大的机制增加了细胞能水平，并确定增加ATP是否会提高功能和易受能量衰竭疾病的人类细胞的存活。我们将实现这些目标在两个具体目标中。（1）我们将使用代谢组学，转录组学和能源生产的测定法和消耗以确定可以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水平的广泛细胞机制， ii）开始评估增加能量水平以防止能量失败的治疗潜力代谢上脆弱的人类细胞。