The role of ATM in Metabolic Stress Responses

ATM 在代谢应激反应中的作用

• 批准号: 9288133
• 负责人: Michael B Kastan
• 金额: $ 37.76万
• 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/9288133
• 关键词: ATM activation; ATM deficient; ATM function; ATM gene; Ataxia Telangiectasia; Ataxia Telangiectasia Patients; B-Lymphocytes; 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; Ions; 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; ataxia telangiectasia mutated protein; biological adaptation to stress; cell type; chelation; clinical phenotype; deprivation; experimental study; gene product; insight; irradiation; metabolic phenotype; mitochondrial dysfunction; novel; novel strategies; novel therapeutic intervention; nucleotide metabolism; organic acid; protein function; 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蛋白激酶被公认为是调节细胞反应的中心信号分子 DNA断裂。ATM基因突变的患者有毁灭性的临床疾病，共济失调-毛细血管扩张症， 有各种医学问题，包括神经退行性变，免疫缺陷，癌症易感性， 胰岛素抵抗和毛细血管扩张的发展。我们实验室和其他实验室的最新数据表明 ATM蛋白激酶也是线粒体功能和代谢信号的关键中介。 尽管ATM缺陷细胞对电离辐射的显著敏感性是公认的，但一个主要的和 在最近这笔赠款的资助期内有一个意想不到的发现，ATM缺陷细胞也 对代谢压力非常敏感，特别是对基本营养物质葡萄糖的耗尽。发现了 ATM缺陷细胞对葡萄糖缺乏的极端敏感性为研究提供了一个新的重要工具 ATM在代谢信号中的作用。值得注意的是，ATM在这些压力反应中的暗示是一种 与ATM和A-T的一般概念大相径庭，但澄清了这些意想不到的角色 ATM在代谢信号中的作用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，比如帕金森氏症，以及代谢异常， 比如2型糖尿病和代谢综合征。提供的初步数据显示了深刻的 ATM缺陷细胞对葡萄糖缺乏的敏感性，即葡萄糖限制激活ATM激酶， 记录了A-T细胞的一系列基础和适应性代谢异常，以及一些意想不到的 挽救A-T细胞代谢敏感性的干预措施，如2-脱氧葡萄糖治疗，过量 谷氨酰胺和活性金属络合。前两种救援方法指向了NADPH的变化 调节作为A-T细胞代谢敏感性的中心调节因子。使用这个模型系统，我们还确定了一个 ATM激酶的新底物，似乎参与了这一代谢调节。实验是 建议进一步探讨ATM在调节线粒体功能中的生化和分子作用 和代谢信号机制。成功完成拟议的实验可能会带来新的 对ATM蛋白这些意想不到的细胞功能的洞察并建立共同的新范例 A-T中促进癌症发展、神经变性和代谢异常的机制 和其他障碍。耐人寻味的是，一种基因产物似乎处于两种DNA损伤的结合点 信号和代谢信号，但也许这并不奇怪，这些核苷酸的调节 新陈代谢和DNA损伤信号将以某种方式联系在一起，在这种情况下，通过自动取款机。这样的洞察力 可以使调节这些通路的新方法成为可能，这既可以促进研究 研究并有可能导致开发新的治疗方法来治疗房颤和其他 常见病。