Molecular mechanisms of lung disease in ataxia telangiectasia

共济失调性毛细血管扩张性肺部疾病的分子机制

• 批准号: 8040274
• 负责人: JoAnn Sekiguchi
• 金额: $ 38.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-03 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040274
• 关键词: A Mouse; ATM gene; ATM wt Allele; Acetylcysteine; Affect; Alleles; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Applications Grants; Ataxia Telangiectasia; Attenuated; Biological Models; Bleomycin; Cause of Death; Cell Cycle Checkpoint; Cell Line; Cell physiology; Cells; Cerebellar Ataxia; Childhood; Chronic; Chronic lung disease; Copper; DNA Damage; DNA Double Strand Break; DNA Repair; Defect; Development; Disease; Disease Progression; Double Strand Break Repair; Effectiveness; Event; Fibrosis; Foundations; Funding Opportunities; Genes; Goals; Human; Hypersensitivity; Immunodeficiency and Cancer; Immunologic Deficiency Syndromes; Individual; Infection; Inherited; Injury; Interstitial Lung Diseases; Investigation; Lead; Lung; Lung diseases; Malignant Neoplasms; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Mutate; Nerve Degeneration; Oxidants; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Predisposition; Prevalence; Protein-Serine-Threonine Kinases; Pulmonary Fibrosis; Reactive Oxygen Species; Recurrence; Regulation; Request for Proposals; Research Proposals; Role; Structure of parenchyma of lung; Study models; Symptoms; System; Teenagers; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; ataxia telangiectasia mutated protein; base; cell type; disease phenotype; disease-causing mutation; effective therapy; insight; lung injury; mortality; mouse model; mutant; novel; outcome forecast; oxidative damage; prevent; progressive neurodegeneration; research study; response; tetrathiomolybdate

DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a rare, autosomal recessive human disorder characterized by cerebellar ataxia, immunodeficiency, cancer predisposition, recurrent sinopulmonary infections and chronic interstitial lung disease. The prognosis for this childhood disease is poor, and most patients do not survive beyond their teens. The most debilitating feature of A-T is progressive neurodegeneration; however, in addition to cancer, one of the leading causes of morbidity and mortality is respiratory system disease, including interstitial lung disease (ILD). Despite the prevalence of ILD as a cause of death in A-T patients, the underlying mechanisms that lead to this phenotype are not well understood. The gene mutated in A-T, ataxia-telangiectasia mutated (ATM), has been identified and encodes a large serine-threonine protein kinase. ATM is considered a "master controller" of cellular responses to DNA double strand breaks, and it is required for activation of cell cycle checkpoints, direct DNA repair events and/or apoptosis. ATM also plays important roles in the control of oxidative stress, and ATM deficiency leads to increased levels of highly reactive oxygen species as well as defects in antioxidant systems. Thus, the pleiotropic phenotypes observed in A-T patients, including ILD, are hypothesized to result from defective responses to DNA damage and/or the consequences of accumulated oxidative damage in mutant cells. The overall goals of this proposal are to elucidate the cellular and molecular mechanisms underlying ILD in A-T patients and to identify potential therapeutics to prevent or effectively treat this potentially fatal disease phenotype. To achieve these goals, we propose the following aims: (1) Develop and characterize a mouse model of A-T ILD using well-established and characterized methods to induce pulmonary fibrosis in animals. We have generated a conditionally inactivatable allele of ATM that can be deleted in specific tissues. Using this unique model system, we can examine the involvement of particular tissues and cell types in the initiation and progression of A-T lung disease; (2) Elucidate the roles of ATM in DNA damage responses in the lung and primary lung cell lines; and (3) Examine the efficacy of possible therapeutics on pulmonary fibrosis in the mouse model of A-T ILD. Together these studies will provide important insights into the causes of lung disease in A-T individuals and establish the effectiveness of potential treatments. In addition, our studies will define the DNA damage responses in the lung, findings that not only have relevance to phenotypes of A-T patients, but also to understanding the molecular bases underlying the severe lung toxicity caused by some chemotherapeutics. PUBLIC HEALTH RELEVANCE: Ataxia-telangiectasia (A-T) is an inherited childhood disease characterized by severe neurodegeneration, cancer predisposition, immunodeficiency and chronic lung disease. One of the most common causes of mortality in these patients is respiratory disease; however, this feature of A-T is not well understood. Thus, the goals of this research proposal are to gain a better understanding of the causes of chronic lung disease in these patients and to identify effective therapeutic strategies to treat this fatal symptom.

描述（由申请人提供）：共济失调-毛细血管扩张症（a-t）是一种罕见的常染色体隐性人类疾病，其特征是小脑性共济失调、免疫缺陷、癌症易感性、复发性肺感染和慢性间质性肺疾病。这种儿童疾病的预后很差，大多数患者活不过十几岁。A-T最衰弱的特征是进行性神经变性；然而，除癌症外，导致发病和死亡的主要原因之一是呼吸系统疾病，包括间质性肺疾病（ILD）。尽管在a - t患者中，ILD是一种常见的死亡原因，但导致这种表型的潜在机制尚不清楚。在a-t中突变的基因，共济失调-毛细血管扩张突变（ataxia- telangi扩张突变，ATM），已经被确定并编码一个大的丝氨酸-苏氨酸蛋白激酶。ATM被认为是细胞对DNA双链断裂反应的“主控制器”，是激活细胞周期检查点、直接DNA修复事件和/或细胞凋亡所必需的。ATM在控制氧化应激中也起着重要作用，而ATM缺乏会导致高活性氧水平的增加以及抗氧化系统的缺陷。因此，在A-T患者中观察到的多性表型，包括ILD，被假设是由于突变细胞对DNA损伤和/或累积氧化损伤的反应缺陷造成的。本提案的总体目标是阐明A-T患者ILD的细胞和分子机制，并确定潜在的治疗方法来预防或有效治疗这种潜在致命的疾病表型。为了实现这些目标，我们提出以下目标：(1)利用成熟和特征化的方法在动物中诱导肺纤维化，建立并表征a - t ILD小鼠模型。我们已经生成了一个ATM的条件不激活等位基因，可以在特定的组织中被删除。使用这个独特的模型系统，我们可以检查特定组织和细胞类型在A-T肺部疾病的发生和进展中的参与；(2)阐明ATM在肺和原代肺细胞系DNA损伤反应中的作用；(3)研究可能的治疗方法对A-T型ILD小鼠模型肺纤维化的疗效。总之，这些研究将为A-T个体肺部疾病的病因提供重要的见解，并确定潜在治疗的有效性。此外，我们的研究将定义肺中的DNA损伤反应，这些发现不仅与A-T患者的表型相关，而且还有助于了解某些化疗药物引起的严重肺毒性的分子基础。