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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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人类疾病，其特征是小脑共济失调、免疫缺陷、癌症倾向、复发性鼻窦肺部感染和慢性间质性肺炎肺部疾病。这种儿童疾病的预后很差，大多数患者无法生存青少年。 A-T 最令人衰弱的特征是进行性神经变性。然而，除了癌症之外，发病和死亡的主要原因之一是呼吸系统疾病，包括间质性肺病疾病（ILD）。尽管 ILD 是 A-T 患者死亡的常见原因，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)，已被鉴定并编码一种大的丝氨酸-苏氨酸蛋白激酶。 ATM被视为“大师” 细胞对 DNA 双链断裂反应的控制器”，它是细胞周期激活所必需的检查点、直接 DNA 修复事件和/或细胞凋亡。 ATM 在控制方面也发挥着重要作用氧化应激和 ATM 缺乏会导致高活性氧的水平增加以及抗氧化系统的缺陷。因此，在 A-T 患者（包括 ILD）中观察到的多效性表型是推测是由于对 DNA 损伤的反应缺陷和/或累积的后果造成的突变细胞的氧化损伤。该提案的总体目标是阐明潜在的细胞和分子机制 A-T 患者中的 ILD 并确定潜在的治疗方法来预防或有效治疗这种可能致命的疾病疾病表型。为了实现这些目标，我们提出以下目标：（1）开发并表征 A-T ILD 小鼠模型使用成熟且特征化的方法诱导肺纤维化动物。我们已经生成了 ATM 的条件失活等位基因，可以在特定组织中删除该等位基因。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 A-T 肺病的发生和进展； (2) 阐明ATM在DNA损伤反应中的作用肺和原代肺细胞系； (3) 检查可能的治疗方法对肺纤维化的疗效 A-T ILD小鼠模型。这些研究将共同为肺部疾病的病因提供重要的见解。 A-T 个体中的疾病并确定潜在治疗的有效性。此外，我们的研究将定义了肺部的 DNA 损伤反应，这些发现不仅与 A-T 表型相关患者，还可以了解某些药物引起的严重肺毒性的分子基础化疗。