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

项目总结(见说明)： 一种关于特发性肺纤维化(IPF)病因和发病机制的新理论是基于II型肺泡上皮细胞(AECII)的慢性损伤、异常修复和凋亡的概念，AECII是分泌表面活性物质的特化肺细胞。由于AECII是含有高度活跃的内质网(ER)细胞器的专业分泌细胞，我们推测当蛋白质折叠能力耗尽时，无数上游的INSET可能会产生内质网应激。一种称为未折叠蛋白反应(UPR)的信号通路提供了对内质网应激的适应，但如果应激是不可修复的，它可能会矛盾地导致细胞凋亡。我们已经学会了用我们开发的新型小分子UPR调制器来防止UPR的关键破坏性输出。在这篇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)来测试一个新的假说，即ER应激诱导的AECIIs的凋亡通过改善凋亡过程和潜在地改变这种致命疾病的进展而在IPF的发展中起关键作用。我们将在3个肺纤维化小鼠模型中评估我们最有效和最特异的UPR调节剂，一个涉及小剂量博莱霉素和衣霉素诱导DNA损伤和内质网(ER)应激，另一个涉及小剂量博莱霉素在表达表面活性蛋白C突变与患者肺纤维化相关的小鼠中的作用，第三个涉及Hermansky Pudlak综合征遗传模型中ER和溶酶体应激的诱导。我们还将评估这些抑制剂对来自正常肺的小鼠AECII和人类AECII以及从人类细胞和组织核心获得的IPF患者的AECII的有效性。我们还将利用应激的AECIIs和BAL以及来自纵向队列核心的血液样本来评估我们发现受UPR调控的microoRNAs作为这一途径的机械信息生物标志物的实用性。在这项工作的基础上，我们希望在PPG的第二阶段确定要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.