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）是一种预后不良的毁灭性疾病， 在过去10年中，美国退伍军人中IPF的发病率和患病率均有所增加， 年此外，急性肺损伤后肺纤维化的发生 在COVID-19的幸存者中尤为突出。致病机制的基础， 纤维化的发展尚未完全了解。基本过程发展 由于遗传异常和/或环境因素，导致重复性损伤， 肺泡上皮，上皮修复机制失调，成纤维细胞增加 和产生过量细胞外基质的（抗骨化）肌成纤维细胞。IPF是 男性比女性更普遍，但差异的原因并不清楚 明白凋亡信号调节激酶1（apoptosis signal regulating kinase 1，ASK 1）是一种促分裂原活化蛋白激酶 激酶激酶（MAP 3 K5），由氧化应激激活并引起MAPK刺激 通路，但下游信号通路是高度组织依赖性的， 在肺纤维化的背景下进行了研究。本申请的总体目标 是为了确定ASK 1是肺纤维化发展的中心介质。的 该建议的中心假设是ASK 1通过p38介导的肺纤维化促进肺纤维化。 炎症和刺激ERK 1/2介导的途径，这些途径是 部分由性激素调节。拟议研究的理由是， 将ASK 1鉴定为纤维化发展中的中心调节因子将促进我们的研究。 对IPF的基本理解并为治疗IPF提供新的治疗选择 患者将使用ASK 1缺陷小鼠和ASK 1小鼠来研究这些机制 抑制剂在博来霉素诱导的纤维化小鼠模型中的作用。此外，肺泡上皮细胞的原代培养 II型上皮细胞和成纤维细胞，以及ASK 1和其他关键基因敲低的细胞系， 介质，将用于定义特定的ASK 1依赖性途径。目标1将测试 纤维化是由激活p38信号的重复氧化应激加剧的假说 通过ASK 1，这些途径受到性激素的调节。目标2将测试 假设ASK 1和ERK 1/2激活性别依赖性差异刺激促纤维化 途径。这些研究将推进我们对纤维化和性的基本理解 差异，并建立ASK 1作为潜在的治疗靶点，以减少进展， IPF。