Sex differences in ASK1-mediated pulmonary fibrosis

特发性肺纤维化(IPF)是一种严重的疾病，预后差。 在过去的10年里，美国退伍军人中IPF的发病率和流行率都有所上升 好几年了。此外，急性肺损伤后肺纤维化的发生 在新冠肺炎的幸存者中表现突出。本病的发病机制 纤维化的发生发展尚不完全清楚。基本流程的发展 由于遗传异常和/或环境因素导致对 肺泡上皮、失调的上皮修复机制和成纤维细胞的增加 和(抗凋亡)肌成纤维细胞产生过多的细胞外基质。IPF是 在男性中比在女性中更常见，但这种差异的原因尚不清楚 明白了。细胞凋亡信号调节蛋白1(ASK1)是一种有丝分裂原激活的蛋白激酶 激酶(MAP3K5)，由氧化应激激活，刺激MAPK 途径，但下游的信号通路是高度组织依赖的，没有 在肺纤维化的背景下进行了研究。本应用程序的总体目标是 目的是确定ASK1是肺纤维化发生发展的中心介质。这个 这一理论的中心假设是ASK1通过p38介导促进肺纤维化。 炎症和刺激ERK1/2介导的通路，这些通路是 部分受性荷尔蒙调节。建议进行研究的理由是 确认ASK1是纤维化发展中的中央调节因子将促进我们的 对特发性肺纤维化的基本认识和新的治疗方案 病人。这些机制将使用ASK1缺陷小鼠和ASK1 博莱霉素诱导的小鼠纤维化模型中的抑制剂。此外，肺泡的原代培养 II型上皮细胞和成纤维细胞，以及ASK1等关键基因被敲除的细胞系 介体，将用于定义特定的ASK1依赖通路。目标1将测试 反复氧化应激激活p38信号通路加剧肝纤维化的假说 通过ASK1，这些途径受性激素调节。目标2将测试 ASK1和ERK1/2激活的性别差异刺激促纤维化的假说 小路。这些研究将促进我们对纤维化和性的基本理解 差异，并建立ASK1作为一个潜在的治疗靶点，以减缓进展 IPF。

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.