ATM, REACTIVE OXYGEN, AND CELLULAR RESPONSES TO HYPOXIA

ATM、活性氧和细胞对缺氧的反应

基本信息

批准号：
8597947
负责人：
Michael B Kastan
金额：
$ 25.28万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597947
关键词：
10 year old ATM gene ATM wt Allele Affect Aging Alleles Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase Autophagocytosis Binding Biochemical Biogenesis Cardiovascular Diseases Cell Cycle Progression Cell Survival Cell physiology Cells Clinical DNA DNA Damage DNA Double Strand Break DNA Repair Data Development Diabetes Mellitus Disease Family Functional disorder Genes Human Hypersensitivity Hypoxia Immune Immunodeficiency and Cancer Immunologic Deficiency Syndromes In Vitro Incidence Individual Insulin Resistance Investigation Laboratories Lead Link Malignant Neoplasms Malignant lymphoid neoplasm Mediator of activation protein Medical Medicine Metabolic Mitochondria Mus Mutagenesis Mutate Nerve Degeneration Oxidative Stress Oxygen Pathogenesis Patients Pharmaceutical Preparations Phosphotransferases Play Predisposition Premature aging syndrome Protein Kinase Proteins Reactive Oxygen Species Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Stress Symptoms Telangiectasis Tissues Wheelchairs ataxia telangiectasia mutated protein cancer therapy human disease in vivo innovation insight irradiation nervous system disorder novel novel strategies novel therapeutic intervention oxidative damage patient population prevent public health relevance research study response

项目摘要

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.

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，并影响多种人类疾病的发展。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，从神经系统疾病到衰老。信号转导途径的诱导是细胞对这些应激反应的一个关键方面，近年来在阐明此类信号转导途径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，从而可以加强研究，并有可能开发出预防和治疗这些疾病的新药。 ATM 蛋白激酶是调节细胞对 DNA 断裂反应的核心信号分子。 ATM 基因突变的患者患有一种被称为共济失调毛细血管扩张症的破坏性临床疾病，并有多种医学问题，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。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 损伤反应异常造成的。一项新的提议认为，线粒体异常和细胞对缺氧应激的反应异常导致活性氧水平升高，导致共济失调毛细血管扩张症患者出现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，并且在缺乏 ATM 的小鼠和人类细胞和组织中发现了线粒体异常。有趣的是，自噬相关基因 beclin 的单个等位基因的缺失部分挽救了缺乏 ATM 的小鼠的活性氧、线粒体和癌症易感性的异常。实验旨在进一步探索 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。初步数据还表明，缺乏 ATM 功能的细胞对缺氧应激有异常反应。实验旨在探索 ATM 损失的机制，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。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对 ATM 蛋白的意外细胞功能产生新的见解，并为导致癌症发展、神经退行性变和代谢异常的常见机制建立新的范例。