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: 8204498
• 负责人: JoAnn Sekiguchi
• 金额: $ 38.6万
• 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/8204498
• 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

PROJECT SUMMARY 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.

项目摘要 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遗传疾病，其特征是小脑 共济失调、免疫缺陷、癌症易感性、复发性鼻窦炎感染和慢性间质性 肺病。这种儿童疾病的预后很差，大多数患者不能存活超过他们的年龄。 十几岁A-T最令人衰弱的特征是进行性神经变性;然而，除了癌症， 发病率和死亡率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ILD作为A-T患者死亡原因的患病率，但其潜在机制 导致这种表型的原因尚不清楚。A-T基因突变，共济失调-毛细血管扩张症突变 (ATM)已鉴定并编码大丝氨酸-苏氨酸蛋白激酶。ATM被认为是“大师 它是细胞对DNA双链断裂反应的“控制器”，是细胞周期激活所必需的 检查点、直接DNA修复事件和/或凋亡。ATM还在控制 氧化应激和ATM缺乏导致高活性氧水平增加， 抗氧化系统的缺陷。因此，在A-T患者（包括ILD）中观察到的多效性表型是 假设是由于对DNA损伤的缺陷反应和/或累积的 突变细胞的氧化损伤。 这项建议的总体目标是阐明潜在的细胞和分子机制， A-T患者的ILD，并确定潜在的治疗方法，以预防或有效治疗这种可能致命的 疾病表型为了实现这些目标，我们提出了以下目标：（1）开发和表征 A-T ILD小鼠模型，使用成熟和表征的方法诱导肺纤维化， 动物我们已经产生了ATM的条件失活等位基因，可以在特定组织中删除。 使用这种独特的模型系统，我们可以检查特定组织和细胞类型在肿瘤中的参与。 （2）探讨ATM在A-T肺疾病发生、发展中的作用; 肺和原代肺细胞系;和（3）检查可能的治疗剂对肺纤维化的功效， A-T ILD小鼠模型。这些研究将共同为肺结核的病因提供重要的见解。 A-T个体的疾病，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表型相关， 患者，但也了解分子基础的严重肺毒性引起的一些 化疗药物