Sex differences in ASK1-mediated pulmonary fibrosis

ASK1介导的肺纤维化的性别差异

• 批准号: 10582848
• 负责人: CHRISTOPHER M WATERS
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582848
• 关键词: Acute Lung Injury; Aging; Alveolar; Apoptosis; Bleomycin; COVID-19 survivors; Cell Culture Techniques; Cell Line; Cessation of life; Chronic Disease; Data; Development; Diagnosis; Disease; Disease Progression; Environmental Risk Factor; Epithelial Cells; Epithelium; Estrogen Receptors; Exposure to; Extracellular Matrix; Extracellular Signal Regulated Kinases; Female; Fibroblasts; Fibrosis; Gases; Goals; Gonadal Steroid Hormones; Hyperoxia; Incidence; Inflammation; Injury; JUN gene; Knowledge; Life Expectancy; Lipopolysaccharides; MAP Kinase Gene; MAP Kinase Kinase Kinase; MAP3K5 gene; MAPK3 gene; MAPK8 gene; Macrophage; Mechanical ventilation; Mediating; Mediator; Mesenchymal; Modeling; Molecular Abnormality; Morbidity - disease rate; Mus; Myofibroblast; NADPH Oxidase; Oxidative Stress; Oxygen; Pathogenicity; Pathway interactions; Patients; Phosphothreonine; Pirfenidone; Prevalence; Process; Prognosis; Proteins; Pulmonary Fibrosis; Regulation; Reporting; Research; Resistance; Role; Sex Differences; Signal Pathway; Signal Transduction; Survivors; TXN gene; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Veterans; Woman; alveolar epithelium; epithelial injury; epithelial repair; fibrotic lung; idiopathic pulmonary fibrosis; improved; inhibitor; knock-down; lung injury; male; men; mortality; mouse model; new therapeutic target; nintedanib; novel; novel therapeutic intervention; novel therapeutics; p38 Mitogen Activated Protein Kinase; response; severe COVID-19; sex; targeted treatment; therapeutic target

Idiopathic pulmonary fibrosis (IPF) is a devastating illness with a poor prognosis, and both the incidence and prevalence of IPF among U.S. Veterans has increased during the last 10 years. In addition, the occurrence of pulmonary fibrosis developing following acute lung injury has been prominent in survivors of COVID-19. The pathogenic mechanisms underlying the development of fibrosis are not completely understood. The fundamental processes develop due to genetic abnormalities and/or environmental factors that lead to repetitive injury to the alveolar epithelium, dysregulated epithelial repair mechanisms, and an increase in fibroblasts and (apoptosis-resistant) myofibroblasts that produce excessive extracellular matrix. IPF is more prevalent in men than in women, but the reasons for the differences are not well understood. Apoptosis signal regulating kinase 1 (ASK1) is a mitogen activated protein kinase kinase kinase (MAP3K5) that is activated by oxidative stress and causes stimulation of MAPK pathways, but the downstream signaling pathways are highly tissue dependent and have not been investigated in the context of pulmonary fibrosis. The overall objective of this application is to establish that ASK1 is a central mediator of the development of pulmonary fibrosis. The central hypothesis of this proposal is that ASK1 promotes pulmonary fibrosis by p38-mediated inflammation and stimulation of ERK1/2-mediated pathways, and that these pathways are regulated in part by sex hormones. The rationale for the proposed research is that the identification of ASK1 as a central regulator in the development of fibrosis will advance our fundamental understanding and lead to new therapeutic options for the treatment of IPF patients. These mechanisms will be investigated using both ASK1-deficient mice and an ASK1 inhibitor in a bleomycin-induced fibrosis mouse model. In addition, primary cultures of alveolar type II epithelial cell and fibroblasts, as well as cell lines with knockdown of ASK1 and other key mediators, will be used to define specific ASK1-dependent pathways. Aim 1 will test the hypothesis that fibrosis is exacerbated by repetitive oxidative stress that activates p38 signaling via ASK1, and that these pathways are regulated by sex hormones. Aim 2 will test the hypothesis that sex-dependent differences in ASK1 and ERK1/2 activation stimulate pro-fibrotic pathways. These studies will advance our fundamental understanding of fibrosis and sex differences and establish ASK1 as a potential therapeutic target to reduce the progression of IPF.

特发性肺纤维化（IPF）是一种毁灭性的疾病，预后不良， 美国退伍军人中IPF的发病率和患病率在过去10个 年。另外，急性肺损伤后发生肺纤维化的发生 在Covid-19的幸存者中一直很突出。依据的致病机制 纤维化的发展尚不完全了解。基本过程发展 由于遗传异常和/或环境因素，导致重复损伤 牙槽上皮，上皮修复机制失调，成纤维细胞增加 和（抗凋亡）的肌纤维细胞，产生过多的细胞外基质。 IPF是 男性比女性更普遍，但差异的原因不好 理解。调节激酶1（ASK1）的凋亡信号是有丝分裂原活化蛋白激酶 激酶激酶（MAP3K5）被氧化应激激活并引起MAPK刺激 途径，但是下游信号通路是高度组织依赖性的，没有 在肺纤维化的背景下进行了研究。该应用程序的总体目标 是为了确定Ask1是肺纤维化发展的中心介体。这 该提议的中心假设是，Ask1促进了P38介导的肺纤维化 ERK1/2介导的途径的炎症和刺激，这些途径是 部分由性激素调节。拟议研究的理由是 识别Ask1作为纤维化发展中的中央调节剂将推动我们的 基本的理解并导致治疗IPF的新治疗选择 患者。这些机制将使用ASK1缺陷小鼠和Ask1进行研究 博来霉素诱导的纤维化小鼠模型中的抑制剂。另外，牙槽的一级培养 II型上皮细胞和成纤维细胞，以及具有敲除ask1和其他钥匙的细胞系 介体将用于定义特定的ask1依赖性途径。 AIM 1将测试 假设纤维化因激活p38信号的重复氧化应激而加剧了纤维化 通过Ask1，这些途径受性激素调节。 AIM 2将测试 假设ASK1和ERK1/2激活中的性别依赖性差异刺激促纤维化 途径。这些研究将提高我们对纤维化和性别的基本理解 差异并建立Ask1作为降低进展的潜在治疗靶标 IPF。