DNA-Damage Repair In Pulmonary Fibrosis

肺纤维化中的 DNA 损伤修复

基本信息

批准号：
9013893
负责人：
Jonathan Andrew Kropski
金额：
$ 3.73万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013893
关键词：
3-Dimensional Abnormal DNA Repair Affect Age Alveolar Bioinformatics Bleomycin Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Line Cell Proliferation Cell Survival Cell model Cells Clinical Complex DNA Damage DNA Repair DNA Repair Pathway Data Development Disease Epithelial Epithelial Cells Family Fibrosis Functional disorder Genes Genetic Risk Hamman-Rich syndrome Histopathology Homologous Gene Injury Interstitial Pneumonia Investigation Length Leukocytes Link Lymphocyte Mediating Modeling Mus Mutation Pathogenesis Pathway interactions Patients Play Predisposition Pulmonary Fibrosis Role Signal Transduction Suggestion Syndrome TP53 gene Telomerase Telomere Shortening Testing alveolar epithelium base exome sequencing genetic risk factor genetic variant helicase insight kindred loss of function loss of function mutation mouse model peripheral blood programs public health relevance rare variant repaired response response to injury telomere

项目摘要

DESCRIPTION (provided by applicant): Up to 20% of idiopathic pulmonary fibrosis cases (IPF) are familial, comprising a syndrome known as Familial Interstitial Pneumonia (FIP). Short peripheral blood telomere length has been associated with sporadic IPF and FIP, and rare loss of function mutations in telomerase complex genes have been found in 15-20% of FIP families, however, investigations to date regarding the mechanisms linking telomerase dysfunction and telomere shortening with lung fibrosis have been largely unrevealing. Using whole-exome sequencing, we have recently identified loss-of-function mutations in regulator of telomere elongation helicase (RTEL1) that segregated with disease in 15 FIP families, and our preliminary data suggest impaired RTEL1 function leads to inefficient repair of DNA-damage in alveolar epithelial cells (AECs), leading to activation of p53 mediated cell- cycle arrest signalin programs that may contribute to AEC dysfunction in the context of pulmonary fibrosis. Using bioinformatics approaches, we identified a large group of FIP families (>50%) that carry rare variants in other genes related to cell cycle, DNA damage-repair, and p53 signaling, suggesting that abnormalities in these interrelated pathways may underlie genetic risk for a large subset of FIP families. In this proposal, we hypothesize that loss-of-function genetic variants in FIP-associated genes (including RTEL1) predispose to pulmonary fibrosis by altering DNA-damage repair and activating p53-mediated cell-cycle checkpoint arrest signaling in alveolar epithelial cells, resulting in impaired re-epithelialization following injury and progressive fibrotic remodeling. Our specific aims are: (1) To determine the role of Rtel in experimental lung fibrosis. (2) To determine the mechanisms through which RTEL1 regulates DNA damage-repair and cell survival/proliferation in response to injury, and (3) To determine whether DNA damage-repair capacity is altered in a large subset of FIP families and patients with sporadic IPF. To accomplish these aims, we will utilize Rtel deficient mouse models, RTEL1 deficient cell lines, primary cells from Rtel deficient mice, and primary cells from FIP and IPF patients. Together, these studies hold the promise of elucidating the role of DNA-damage repair and signaling in the development of pulmonary fibrosis, thus adding important new insights into disease pathogenesis.

描述（由申请人提供）：高达 20% 的特发性肺纤维化病例 (IPF) 是家族性的，包括一种称为家族性间质性肺炎 (FIP) 的综合征，外周血端粒长度短与散发性 IPF 和 FIP 相关，但这种情况很少见。在 15-20% 的 FIP 家族中发现了端粒酶复合体基因的功能缺失突变，然而，迄今为止的研究尚未证实其机制端粒酶功能障碍和端粒缩短与肺纤维化之间的联系在很大程度上尚未被揭示，利用全外显子组测序，我们最近在 15 个 FIP 家族中发现了与疾病分离的端粒延长解旋酶调节因子 (RTEL1) 的功能丧失突变。初步数据表明，RTEL1 功能受损会导致肺泡上皮细胞 (AEC) 中 DNA 损伤的修复效率低下，从而导致肺泡上皮细胞 (AEC) 的激活p53 介导的细胞周期停滞信号程序可能导致肺纤维化背景下的 AEC 功能障碍。使用生物信息学方法，我们鉴定了一大群 FIP 家族 (>50%)，它们在与细胞周期相关的其他基因中携带罕见变异。 DNA 损伤修复和 p53 信号传导，表明这些相互关联的途径的异常可能是 FIP 家族一大子集的遗传风险的基础。在这项提议中，我们迫切希望发现 FIP 相关的功能丧失遗传变异。基因（包括 RTEL1）通过改变 DNA 损伤修复和激活肺泡上皮细胞中 p53 介导的细胞周期检查点停滞信号传导而诱发肺纤维化，导致损伤后上皮再形成受损和进行性纤维化重塑。 1) 确定 Rtel 在实验性肺纤维化中的作用 (2) 确定 RTEL1 调节 DNA 损伤修复和细胞存活/增殖的机制。 (3) 为了确定 FIP 家族和散发性 IPF 患者的 DNA 损伤修复能力是否发生改变，为了实现这些目标，我们将利用 Rtel 缺陷小鼠模型、RTEL1 缺陷细胞系，来自 Rtel 缺陷小鼠的原代细胞以及来自 FIP 和 IPF 患者的原代细胞，这些研究有望阐明 DNA 损伤修复和信号传导在肺纤维化发展中的作用，从而为肺纤维化的发展提供重要的新见解。疾病发病机制。