The role of ATM in Metabolic Stress Responses

ATM 在代谢应激反应中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 ATM 蛋白激酶是公认的调节细胞响应的中央信号分子。 DNA断裂。 ATM 基因突变的患者患有毁灭性的临床疾病，共济失调毛细血管扩张症，患有各种医疗问题，包括神经退行性变、免疫缺陷、癌症倾向、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传导的关键介质。尽管 ATM 缺陷细胞对电离辐射具有显着敏感性，但一个主要的和在本次资助的最近资助期间取得的意外发现是，ATM 缺陷的细胞也对代谢应激非常敏感，特别是对必需营养素葡萄糖的消耗。的发现 ATM 缺陷细胞对葡萄糖缺乏的极度敏感性为研究提供了一种新颖且重要的工具 ATM 在代谢信号传导中的作用。值得注意的是，ATM 在这些应激反应中的含义是与 ATM 和 A-T 的一般概念有很大的不同，但澄清了这些意想不到的角色代谢信号中的 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（如帕金森病）和代谢异常的因素，例如 2 型糖尿病和代谢综合征。初步数据表明了深刻的 ATM 缺陷细胞对葡萄糖剥夺的敏感性，通过葡萄糖限制激活 ATM 激酶，记录了 A-T 细胞中一系列基础和适应性代谢异常，以及一些意想不到的情况挽救 A-T 细胞代谢敏感性的干预措施，例如 2-脱氧葡萄糖治疗、过量谷氨酰胺和活性金属螯合。前两种救援方法均指向 NADPH 的改变调节作为 A-T 细胞代谢敏感性的中心介质。使用这个模型系统，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产生新的结果深入了解 ATM 蛋白的这些意想不到的细胞功能，并建立常见的新范式导致 A-T 癌症发展、神经退行性变和代谢异常的机制和其他疾病。有趣的是，一种基因产物似乎与两种 DNA 损伤都有联系。信号传导和代谢信号传导，但也许这并不奇怪，这些核苷酸的调节新陈代谢和 DNA 损伤信号传导会以某种方式联系起来，在这种情况下，是通过 ATM 联系起来的。这样的见解可以采用新的方法来调节这些途径，这既可以加强研究研究并有可能导致开发治疗 A-T 和其他疾病的新治疗方法常见疾病。