The role of ATM in Metabolic Stress Responses

ATM 在代谢应激反应中的作用

• 批准号: 9173446
• 负责人: Michael B Kastan
• 金额: $ 30.21万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173446
• 关键词: ATM activation; ATM deficient; ATM function; ATM gene; Ataxia Telangiectasia; Ataxia Telangiectasia Patients; Biochemical; Biological Models; Cell physiology; Cells; Clinical; Consumption; DNA; DNA Damage; Data; Deoxyglucose; Development; Disease; Documentation; Exhibits; Funding; Gap Junctions; Genes; Glucose; Glutamine; Goals; Grant; Immune; Immunodeficiency and Cancer; Insulin Resistance; Intervention; Lead; Link; Lung diseases; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Metals; Mitochondria; Molecular; Mutate; NADP; Nerve Degeneration; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Null Lymphocytes; Nutrient; Output; Oxidation-Reduction; Palmitates; Parkinson Disease; Pathway interactions; Patients; Pattern; Phosphorylation; Physiological; Play; Predisposition; Process; Recruitment Activity; Regulation; Role; Series; Signal Transduction; Signaling Molecule; Sterility; T-Lymphocyte; Telangiectasis; abstracting; ataxia telangiectasia mutated protein; biological adaptation to stress; cell type; chelation; clinical phenotype; deprivation; gene product; insight; irradiation; metabolic phenotype; mitochondrial dysfunction; novel; novel strategies; novel therapeutic intervention; nucleotide metabolism; organic acid; research study; response; tool

Project Summary/Abstract The ATM protein kinase is well-established as a central signaling molecule in modulating cellular responses to DNA breakage. Patients with mutated ATM genes have a devastating clinical disorder, Ataxia-telangiectasia, with a variety of medical problems, including neurodegeneration, immunodeficiency, cancer predisposition, insulin resistance, and telangiectasia development. Recent data from our lab and others have demonstrated that the ATM protein kinase is also a critical mediator of mitochondrial function and metabolic signaling. Though a significant sensitivity of ATM-defective cells to ionizing irradiation is well-established, a major and unexpected discovery made during the recent funding period of this grant was that ATM-deficient cells are also profoundly sensitive to metabolic stress, notably to depletion of the essential nutrient glucose. The discovery of the extreme sensitivity of ATM-deficient cells to glucose deficiency provides a novel and important tool to study the roles of ATM in metabolic signaling. It is noted that implication of ATM in these stress responses is a significant departure from general concepts about ATM and A-T, but clarifications of these unexpected roles of ATM in metabolic signaling could have impact on general understanding of many disease processes, including those contributing to neurodegenerative disorders, like Parkinson's disease, and to metabolic abnormalities, like type-2 diabetes and metabolic syndrome. Preliminary data is presented demonstrating the profound sensitivity of ATM-deficient cells to glucose deprivation, an activation of the ATM kinase by glucose limitation, documentation of a series of basal and adaptive metabolic abnormalities in A-T cells, and some unexpected interventions which rescue the metabolic sensitivity of A-T cells, such as 2-deoxyglucose treatment, excess glutamine, and reactive metal chelation. The former two rescue approaches point to alterations in NADPH regulation as a central mediator of A-T cell metabolic sensitivity. Using this model system, we also identified a new substrate of the ATM kinase that appears to be involved in this metabolic regulation. Experiments are proposed to further explore the biochemical and molecular roles of ATM in regulating mitochondrial function and metabolic signaling mechanisms. Successful completion of the proposed experiments could lead to new insights into these unexpected cellular functions of the ATM protein and establish new paradigms for common mechanisms that contribute to cancer development, neurodegeneration, and metabolic abnormalities in A-T and other disorders. It is intriguing that one gene product seems to be at a nexus of both DNA damage signaling and metabolic signaling, but perhaps it should not be surprising that these regulation of nucleotide metabolism and DNA damage signaling would be linked in some way, in this case, by ATM. Such insights could enable novel approaches to modulation of these pathways, which can could both enhance research studies and have the potential to lead to development of new therapeutic approaches to treat A-T and other common diseases.

项目摘要/摘要 ATM蛋白激酶在调节细胞对 DNA断裂。突变的ATM基因患者患有灾难性的临床疾病，共济失调性促脑症， 有多种医学问题，包括神经退行性，免疫缺陷，癌症易感性， 胰岛素抵抗和开发性发育。我们实验室和其他人的最新数据已证明 ATM蛋白激酶也是线粒体功能和代谢信号传导的关键介体。 尽管ATM缺陷细胞对电离辐射的显着敏感性是完善的，但主要和 在这笔赠款的最近资助期间，意外的发现是ATM缺陷的细胞也是 对代谢应激非常敏感，特别是对必需营养葡萄糖的消耗。发现 ATM缺乏细胞对葡萄糖缺乏的极端敏感性为研究提供了一种新颖而重要的工具 ATM在代谢信号传导中的作用。注意，ATM在这些压力反应中的影响是 与关于ATM和A-T的一般概念有很大的不同，但阐明了这些意外角色的 代谢信号传导中的ATM可能会影响对许多疾病过程的一般理解，包括 那些导致神经退行性疾病的人，例如帕金森氏病，以及代谢异常， 例如2型糖尿病和代谢综合征。提供了初步数据，证明了深刻的 ATM缺乏细胞对葡萄糖剥夺的敏感性，这是通过葡萄糖限制激活ATM激酶的敏感性， A-T细胞中一系列基础和自适应代谢异常的文献，有些意外 挽救A-T细胞代谢敏感性的干预措施，例如2-脱氧葡萄糖处理，过多 谷氨酰胺和反应性金属螯合。前两个救援方法指出了NADPH的改变 调节是A-T细胞代谢敏感性的中心介体。使用此模型系统，我们还确定了 ATM激酶的新底物似乎参与了这种代谢调节。实验是 提议进一步探索ATM在调节线粒体功能中的生化和分子作用 和代谢信号传导机制。成功完成拟议的实验可能会导致新的 对ATM蛋白的这些意外细胞功能的见解，并为常见建立新的范式 有助于癌症发展，神经退行性和代谢异常的机制 和其他疾病。有趣的是，一个基因产物似乎处于两个DNA损伤的联系 信号传导和代谢信号传导，但可能不足为奇的是，这些调节核苷酸的调节 代谢和DNA损伤信号传导将以某种方式通过ATM链接。这样的见解 可以使新方法调节这些途径，这可以增强研究 研究并有可能导致开发新的治疗方法来治疗A-T和其他 常见疾病。