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

• 批准号: 10622496
• 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
• 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/10622496
• 关键词: Address; Aging; Bioenergetics; Biological Assay; Biosensor; CRISPR interference; CRISPR-mediated transcriptional activation; Cardiac Myocytes; Cell Line; Cell physiology; Cells; Cessation of life; Consumption; Disease; Energy Metabolism; Energy consumption; 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; Leukemic Cell; Libraries; Malignant Neoplasms; Measures; Mediating; Mediator; Metabolic; Mitochondria; Neurodegenerative Disorders; Neurons; Oxygen; Pathway interactions; Predisposition; Production; Respiration; Respiratory physiology; Role; Synapses; Testing; Therapeutic; anti aging; cell type; deprivation; experimental study; high throughput screening; hypoxia inducible factor 1; improved; innovation; metabolomics; preservation; protective effect; respiratory; sensor; transcriptomics; whole genome

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.

项目总结

项目成果

Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.

• DOI: 10.1371/journal.pbio.3001753
• 发表时间: 2022-09
• 期刊: PLOS BIOLOGY
• 影响因子: 9.8
• 作者: Bennett, Neal K.;Nakaoka, Hiroki J.;Laurent, Danny;Okimoto, Ross A.;Sei, Yoshitaka;Horvai, Andrew E.;Bivona, Trever G.;Ten Hoeve, Johanna;Graeber, Thomas G.;Nakamura, Ken;Nakamura, Jean L.
• 通讯作者: Nakamura, Jean L.

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.

• DOI: 10.1038/s41467-023-44033-0
• 发表时间: 2023-12-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Furthmann, Nikolas;Bader, Verian;Angersbach, Lena;Blusch, Alina;Goel, Simran;Sanchez-Vicente, Ana;Krause, Laura J.;Chaban, Sarah A.;Grover, Prerna;Trinkaus, Victoria A.;van Well, Eva M.;Jaugstetter, Maximilian;Tschulik, Kristina;Damgaard, Rune Busk;Saft, Carsten;Ellrichmann, Gisa;Gold, Ralf;Koch, Arend;Englert, Benjamin;Westenberger, Ana;Klein, Christine;Jungbluth, Lisa;Sachse, Carsten;Behrends, Christian;Glatzel, Markus;Hartl, F. Ulrich;Nakamura, Ken;Christine, Chadwick W.;Huang, Eric J.;Tatzelt, Jorg;Winklhofer, Konstanze F.
• 通讯作者: Winklhofer, Konstanze F.

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

• DOI: 10.1002/humu.24453
• 发表时间: 2022-12
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Rius, Rocio;Bennett, Neal K.;Bhattacharya, Kaustuv;Riley, Lisa G.;Yuksel, Zafer;Formosa, Luke E.;Compton, Alison G.;Dale, Russell C.;Cowley, Mark J.;Gayevskiy, Velimir;Al Tala, Saeed M.;Almehery, Abdulrahman A.;Ryan, Michael T.;Thorburn, David R.;Nakamura, Ken;Christodoulou, John
• 通讯作者: Christodoulou, John

The PINK1 advantage: recycling mitochondria in times of trouble?

PINK1 的优势：在遇到麻烦时回收线粒体？

• DOI: 10.1080/15548627.2021.1998872
• 发表时间: 2022
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Doric,Zak;Li,Huihui;Nakamura,Ken
• 通讯作者: Nakamura,Ken

SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19.

人IPSC衍生的心脏细胞的SARS-COV-2感染反映了COVID-19患者心脏的细胞病变特征。

• DOI: 10.1126/scitranslmed.abf7872
• 发表时间: 2021-04-21
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Perez-Bermejo JA;Kang S;Rockwood SJ;Simoneau CR;Joy DA;Silva AC;Ramadoss GN;Flanigan WR;Fozouni P;Li H;Chen PY;Nakamura K;Whitman JD;Hanson PJ;McManus BM;Ott M;Conklin BR;McDevitt TC
• 通讯作者: McDevitt TC