Drugs to combat ER stress-induced dysfunction of AECIIs/Sheppard

项目总结（见说明）： 特发性肺纤维化（IPF）的病因学和发病机制的新兴理论是基于慢性损伤、异常修复和II型肺泡上皮细胞（AECII）（分泌表面活性剂的特化肺细胞）凋亡的概念。由于AECIIs是含有高度活跃的内质网（ER）细胞器的专业分泌细胞，我们假设，无数的上游侮辱可能会产生ER压力，因为蛋白质折叠能力耗尽。一种称为未折叠蛋白反应（UPR）的信号通路提供了对ER应激的适应，但如果应激不可补救，则可能会导致细胞凋亡。我们已经学会了用我们开发的新型小分子UPR调节剂来防止UPR的关键破坏性输出。在本tPPG中，我们建议使用我们的UPR调节剂（以及在药物化学核心中开发的改进版本）来测试一个新出现的假设，即ER应激诱导的AECII细胞凋亡通过改善细胞凋亡过程对IPF的发展至关重要，并可能改变这种致命疾病的进展。我们将在3种肺纤维化小鼠模型中评估我们最有效和特异性的UPR调节剂，一种涉及通过低剂量博来霉素和衣霉素诱导DNA损伤与内质网（ER）应激的组合，另一种通过低剂量博来霉素在表达与患者肺纤维化相关的表面活性蛋白C突变的小鼠中进行，第三个涉及在Hermansky Pudlak综合征的遗传模型中诱导ER和溶酶体应激。我们还将评价这些抑制剂中的每一种对来自正常肺和IPF患者的鼠AECII和人AECII的有效性，所述患者从人细胞和组织中心获得。我们还将利用来自纵向队列核心的应激AECII和BAL和血液样本来评估我们发现由UPR调节的micoRNA作为该途径的机械信息生物标志物的效用。基于这项工作，我们希望在PPG的第二阶段确定在临床试验中测试的药物，以及快速监测这些化合物在患者中的有效性的策略。

PROJECT SUMMARY (See instructions): An emerging theory of the etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF) is based on the concept of chronic injury, aberrant repair, and apoptosis of type II alveolar epithelial cells (AECII), the specialized lung cells that secrete surfactant. As AECIIs are professional secretory cells containing highly active endoplasmic reticulum (ER) organelles, we hypothesize that myriad upstream insults may generate ER stress as protein folding capacity becomes exhausted. A signaling pathway called the unfolded protein response (UPR) affords adaptation to ER stress, but can paradoxically cause apoptosis if the stress is irremediable. We have learned to prevent key destructive outputs from the UPR with novel small molecule UPR modulators that we have developed. In this tPPG, we propose to use our UPR modulators (and improved versions developed in the Medicinal Chemistry Core) to test an emerging hypothesis that ER stress-induced apoptosis of AECIIs is central to development of IPF through ameliorating the apoptotic process, and potentially modifying progression of this deadly disease. We will evaluate our most potent and specific UPR modulators in 3 murine models of pulmonary fibrosis, one involving induction of DNA damage combined with endoplasmic reticulum (ER) stress by low dose bleomycin and tunicamycin, another by low dose bleomycin in mice expressing a surfactant protein C mutation associated with pulmonary fibrosis in patients, and a third involving induction of ER and lyosomal stress in a genetic model of the Hermansky Pudlak Syndrome. We will also evaluate the effectiveness of each of these inhibitors on murine AECIIs and human AECIIs from normal lungs and patients with IPF obtained from the Human Cell and Tissue Core. We will also utilize stressed AECIIs and BAL and blood samples from the Longitudinal Cohort Core to evaluate the utility of micoRNAs we have found to be modulated by the UPR as mechanistically informative biomarkers of this pathway. Based on this work we expect to identify drugs to test in clinical trials in the second phase of this PPG and a strategy for rapidly monitoring the effectiveness of these compounds in patients.