Myofibroblast Senescence in Pulmonary Fibrosis

肺纤维化中的肌成纤维细胞衰老

• 批准号: 8916533
• 负责人: Victor J. Thannickal
• 金额: $ 32.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916533
• 关键词: Accounting; Affect; Age; Aging; Animal Model; Antioxidants; Apoptosis; Applications Grants; Attenuated; Bioenergetics; Biological; Blood Vessels; Cell Aging; Cicatrix; Clinical; Data; Development; Diagnosis; Disease; Enzymes; Equilibrium; Exhibits; FDA approved; Fibroblasts; Fibrosis; Gases; Gene Expression; Genes; Genetic; Hamman-Rich syndrome; Health; Heart; Homeostasis; Human; Human Characteristics; Incidence; Kidney; Laboratories; Lead; Link; Liver; Lung; Lung diseases; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; NADPH Oxidase; Nuclear; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Prevalence; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Research; Resistance; Resolution; Respiratory Failure; Role; Small Interfering RNA; Structure of parenchyma of lung; Survival Rate; Testing; Time; Tissues; age related; aged; body system; burden of illness; effective therapy; fibrogenesis; human subject; impaired capacity; in vivo; inhibitor/antagonist; insight; lung injury; mitochondrial dysfunction; mortality; novel; novel therapeutic intervention; nuclear factor-erythroid 2; older patient; response; senescence; transcription factor

DESCRIPTION (provided by applicant): Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF) is a disease of aging carries a high morbidity and mortality, with a median survival rate of less than three years. There are currently no U.S. FDA-approved anti-fibrotic drugs. The incidence and prevalence of IPF increase drastically with age; however, despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Recent studies from our laboratory indicate that the biological effects of the ROS-generating enzyme, NADPH oxidase-4 (Nox4) is determined by the capacity of myofibroblasts (MFbs) to maintain redox homeostasis via the induction of the antioxidant response transcription factor, nuclear factor-like 2 (Nrf2), a respons that is deficient with aging. Loss of this cellular homeostatic mechanism results in the emergence of a senescent and apoptosis-resistant phenotype of MFbs, at least in part related to mitochondrial dysfunction. Human subjects with IPF exhibit elevated expression of Nox4 and decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. In contrast to self-limited, resolving fibrosis in young mice, aged mice manifest an impaired capacity for resolution of fibrosis. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. The central hypothesis to be tested in this project is that an imbalance of Nox4-Nrf2 induces sustained oxidative stress that induces MFb senescence and apoptosis resistance, leading to persistent fibrosis associated with aging. Our specific aims are to: (1) Determine mechanisms for the (dys)regulation of Nrf2 expression/induction by oxidative stress with cellular senescence; (2) Determine the role of Nox4-Nrf2 imbalance and mitochondrial bioenergetics in promoting Fb senescence; and (3) Determine whether conditional genetic deletion of Nrf2 in Fbs mediates persistent fibrosis in young mice; and whether Nrf2 induction or Nox4 inhibition (by pharmacologic approaches) promotes fibrosis resolution in aged mice. This grant application is responsive to PA-10-014: Development and Characterization of Animal Models for Aging Research. The completion of the aims in this project will: (a) establish a disease-relevant animal model of non-resolving fibrosis; (b) define mechanisms for the loss of redox homeostatic control in MFbs; (c) establish mechanistic links between mitochondrial dysfunction and senescence; and (d) provide proof-of-concept that correction of cellular redox balance will promote fibrosis resolution and lead to the development of novel therapeutic approaches to non-resolving fibrotic disorders such as IPF.

描述（由申请人提供）：人类纤维化疾病会影响许多器官系统，包括心脏，血管，肾脏，肝脏和肺部。特发性肺纤维化（IPF）是最常见的纤维化肺部疾病，是一种衰老的疾病，具有高发病率和死亡率，中位存活率少于三年。目前没有美国FDA批准的抗纤维化药物。 IPF的发病率和患病率随着年龄的增长而大大增加；然而，尽管存在这种牢固的关联，但尚未阐明偏爱纤维性疾病的衰老的细胞/分子机制。 我们实验室的最新研究表明，ROS-生成酶，NADPH氧化酶-4（NOX4）的生物学作用取决于肌成纤维细胞（MFB）通过诱导抗氧化剂转录因子，核因子类似核因子2（NRF2）的诱导来维持氧化还原稳态的能力（MFBS）。这种细胞体内稳态机制的丧失导致MFB的衰老和凋亡抗性表型的出现，至少部分与线粒体功能障碍有关。具有IPF的人类受试者在肌纤维细胞灶中表现出升高的NOX4表达和NRF2表达降低，支持人类纤维化疾病中这种细胞氧化还原不平衡。与在年轻小鼠中自限的纤维化相比，老年小鼠表现出纤维化解决的能力受损。据我们所知，这代表了纤维化的第一个老化模型，该模型概括了人类IPF的不可分析性质。 在该项目中要检验的中心假设是，NOX4-NRF2的失衡会诱导持续的氧化应激，从而诱导MFB衰老和抗凋亡耐药性，从而导致与衰老相关的持续性纤维化。我们的具体目的是：（1）确定通过氧化应激和细胞衰老对NRF2表达/诱导（DYS）调节的机制； （2）确定NOX4-NRF2失衡和线粒体生物能力在促进FB衰老中的作用； （3）确定FBS中NRF2的条件遗传缺失是否介导了小鼠的持续纤维化； NRF2诱导还是NOX4抑制（通过药物方法）促进老年小鼠的纤维化分辨率。 该赠款的应用对PA-10-014的响应敏感：动物模型的发展和表征用于衰老研究。该项目中目标的完成将：（a）建立与疾病相关的非分辨纤维化动物模型； （b）定义MFB中氧化还原稳态控制丧失的机制； （c）在线粒体功能障碍与衰老之间建立机械联系； （d）提供了概念验证，表明细胞氧化还原平衡的校正将促进纤维化的分辨率，并导致开发新的治疗方法，以解决非分辨纤维化疾病，例如IPF。