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损伤和其他应力的反应是细胞活力和诱变的重要决定因素，并影响了广泛的人类疾病的发展。低氧和氧化应激在许多人类疾病的发病机理中也很重要，从癌症到心血管疾病再到神经系统疾病再到衰老。信号转导途径的诱导是细胞对这些应力反应的关键方面，近年来已经取得了重大进步，阐明了此类信号通路中的生化步骤。对此类步骤的澄清可以调节这些反应，从而可以增强研究，并有可能导致开发新药物以预防和治疗这些疾病。 ATM蛋白激酶是调节细胞对DNA断裂反应的中央信号分子。突变ATM基因的患者患有毁灭性的临床疾病，称为共济失调性促性促性促性，并且患有多种医学问题，包括神经退行性，免疫缺陷，癌症易感性，胰岛素抵抗和尾静脉曲张性发育。这里提出的论点说，这些患者的多效异常可能不仅是由于DNA损伤反应异常引起的。提出了一项新的建议，即由线粒体异常引起的活性氧水平增加，细胞对低氧应激的反应异常导致或引起双X省 - telangiectiaia telaxia telangicyciaia患者中许多或所有病理生理状态。提供了初步数据，证实了缺乏ATM功能的细胞中活性氧的水平增加，并且在小鼠，人类细胞和缺乏ATM的组织中鉴定了线粒体异常。有趣的是，自噬相关基因的单个等位基因损失部分挽救了缺乏ATM的小鼠中反应性氧，线粒体和癌症倾向的异常。提出了实验以进一步探索ATM损失导致线粒体异常和活性氧水平的机制，以及Beclin杂合性如何挽救这些异常。初步数据还表明，缺乏ATM功能的细胞中对低氧应激的异常反应。提出了实验来探索ATM损失可能通过对线粒体和活性氧的影响的机制，会影响细胞对低氧应激的反应。将研究ATM在调节HIF-11或HIF-21信号通路中的作用。成功完成所提出的实验可能会导致对ATM蛋白意外细胞功能的新见解，并为有助于癌症发展，神经变性和代谢异常的常见机制建立新的范式。 公共卫生相关性：由于丧失ATM基因产物而导致的一种疾病，患有共济失调性链球菌的患者患有多种医疗问题，包括神经变性，免疫缺陷，过早衰老和癌症的易感性。在此处提出的实验中，我们将探讨为什么ATM功能的损失导致细胞中的氧化应激和损伤，并特别关注其对线粒体功能的影响以及对低氧应激的反应。获得的新见解不仅可能对该患者人群有益，而且还可以使癌症，心血管疾病和神经系统疾病的患者受益。