ATM, REACTIVE OXYGEN, AND CELLULAR RESPONSES TO HYPOXIA

ATM、活性氧和细胞对缺氧的反应

• 批准号: 8368238
• 负责人: Michael B Kastan
• 金额: $ 10.83万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368238
• 关键词: Hypoxia; Oxygen; response

DESCRIPTION (provided by applicant): Cellular responses to DNA damage and other stresses are important determinants of cell viability and mutagenesis and impact the development of a wide range of human diseases. Hypoxic and oxidative stresses are also important in the pathogenesis of many human diseases, ranging from cancer to cardiovascular disease to neurological disorders to aging. Induction of signal transduction pathways is a critical aspect of cellular responses to these stresses and significant advances have been made in recent years elucidating the biochemical steps in such signaling pathways. Clarification of such steps enables modulation of these responses, which can enhance research studies and have the potential to lead to development of new medicines to prevent and treat these diseases. The ATM protein kinase is a central signaling molecule in modulating cellular responses to DNA breakage. Patients with mutated ATM genes have a devastating clinical disorder known as Ataxia-telangiectasia and have a variety of medical problems, including neurodegeneration, immunodeficiency, cancer predisposition, insulin resistance, and telangiectasia development. Arguments are put forth here that the pleiotropic abnormalities in these patients may not simply be due to DNA damage response abnormalities. A novel proposal is made that increased levels of reactive oxygen species, resulting from mitochondrial abnormalities, and abnormalities in cellular responses to hypoxic stresses contribute to or cause many or all of the pathophysiologic states seen in patients with Ataxia-telangiectasia. Preliminary data is presented confirming increased levels of reactive oxygen species in cells lacking ATM function and mitochondrial abnormalities are identified in mouse and human cells and tissues lacking ATM. Interestingly, loss of a single allele of the autophagy-related gene, beclin, partially rescued the abnormalities in reactive oxygen species, mitochondria, and cancer predisposition in mice lacking ATM. Experiments are proposed to further explore the mechanisms by which ATM loss leads to abnormalities in mitochondria and levels of reactive oxygen species and how beclin heterozygosity rescues these abnormalities. Preliminary data also demonstrated abnormal responses to hypoxic stress in cells lacking ATM function. Experiments are proposed to explore the mechanisms by which ATM loss, perhaps through its impact on mitochondria and reactive oxygen species, affects cellular responses to hypoxic stress. The role of ATM in modulating either the Hif-11 or Hif-21 signaling pathways will be investigated. Successful completion of the proposed experiments could lead to new insights into unexpected cellular functions of the ATM protein and establish new paradigms for common mechanisms that contribute to cancer development, neurodegeneration, and metabolic abnormalities. PUBLIC HEALTH RELEVANCE: Patients with Ataxia-telangiectasia, a disease resulting from loss of the ATM gene product, have a wide variety of medical problems, including neurodegeneration, immune deficiencies, premature aging, and cancer predisposition. In experiments proposed here, we will explore why loss of ATM function leads to oxidative stress and damage in cells, with a particular focus on its impact on mitochondrial function and responses to hypoxic stress. New insights gained could be beneficial not only to this patient population, but could also benefit patients with cancer, cardiovascular disease, and neurological disorders.

描述（由申请人提供）：细胞对DNA损伤和其他应激的反应是细胞活力和诱变的重要决定因素，并影响广泛的人类疾病的发展。缺氧和氧化应激在许多人类疾病的发病机制中也很重要，从癌症到心血管疾病到神经系统疾病到衰老。信号转导通路的诱导是细胞对这些应激反应的一个关键方面，近年来在阐明这些信号通路中的生化步骤方面取得了重大进展。澄清这些步骤可以调节这些反应，这可以加强研究，并有可能导致开发预防和治疗这些疾病的新药。ATM蛋白激酶是调节细胞对DNA断裂反应的中心信号分子。ATM基因突变的患者有一种破坏性的临床疾病，称为共济失调-毛细血管扩张症，并有各种各样的医学问题，包括神经变性、免疫缺陷、癌症易感性、胰岛素抵抗和毛细血管扩张的发展。这里提出的论点是，这些患者的多效性异常可能不仅仅是由于DNA损伤反应异常。一项新的研究提出，线粒体异常导致的活性氧水平升高，以及细胞对缺氧应激的异常反应，有助于或导致共济失调毛细血管扩张患者的许多或所有病理生理状态。初步数据证实，缺乏ATM功能的细胞中活性氧水平升高，并且在小鼠和人类缺乏ATM的细胞和组织中发现线粒体异常。有趣的是，在缺乏ATM的小鼠中，自噬相关基因beclin的单个等位基因的缺失部分地挽救了活性氧、线粒体和癌症易感性的异常。为了进一步探索ATM丢失导致线粒体和活性氧水平异常的机制，以及beclin杂合性如何挽救这些异常，我们提出了实验。初步数据还显示，缺乏ATM功能的细胞对缺氧应激的反应异常。研究人员建议通过实验来探索ATM丢失的机制，可能是通过其对线粒体和活性氧的影响，影响细胞对缺氧应激的反应。ATM在调节Hif-11或Hif-21信号通路中的作用将被研究。上述实验的成功完成可能会导致对ATM蛋白意想不到的细胞功能的新见解，并为促进癌症发展，神经变性和代谢异常的共同机制建立新的范例。