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

对抗 ER 应激引起的 AECIIs/Sheppard 功能障碍的药物

基本信息

批准号：
8401271
负责人：
Feroz R Papa
金额：
$ 42.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-09 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401271
关键词：
Alveolar Apoptosis Apoptotic Biochemical Biological Markers Bleomycin Blood specimen Catalytic Domain Cell Survival Cells Cessation of life Chronic Client Clinical Trials DNA Damage Development Disease Dose Drug Delivery Systems Effectiveness Endoplasmic Reticulum Epithelial Cells Etiology Event Exhibits Fibrosis Functional disorder Future Genetic Genetic Models Hamman-Rich syndrome Hermanski-Pudlak Syndrome Homeostasis Human In Vitro Injury Instruction Integral Membrane Protein Learning Link Logic Lung Lung diseases Mediating Messenger RNA Modeling Modification Molecular Chaperones Monitor Mus Mutation Organelles Output Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphotransferases Process Proteins Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein C RNA Splicing Ribonucleases Screening procedure Secretory Cell Signal Pathway Signal Transduction Stress Structure of parenchyma of lung Testing Therapeutic Tissues Translating Tunicamycin Validation Work arm base cohort combat endoplasmic reticulum stress epithelial to mesenchymal transition exhaust human tissue immortalized cell improved in vivo indium-bleomycin inhibitor/antagonist insight kinase inhibitor mRNA Decay mouse model mutant novel pre-clinical prevent programs protein folding repaired research clinical testing response small molecule surfactant theories transcription factor

项目摘要

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.

项目摘要（参见说明）：特发性肺纤维化 (IPF) 病因学和发病机制的新兴理论基于 II 型肺泡上皮细胞 (AECII)（分泌表面活性剂的特殊肺细胞）的慢性损伤、异常修复和凋亡的概念。由于 AECII 是含有高活性内质网 (ER) 细胞器的专业分泌细胞，我们假设随着蛋白质折叠能力耗尽，无数的上游损伤可能会产生 ER 应激。一种称为未折叠蛋白反应（UPR）的信号通路可以适应内质网应激，但如果应激无法缓解，就会矛盾地导致细胞凋亡。我们已经学会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。在这个 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）来测试一个新的假设，即 ER 应激诱导的 AECII 细胞凋亡是通过改善细胞凋亡过程和潜在地改变 IPF 的发展的核心。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，其中一种涉及低剂量博来霉素和衣霉素诱导 DNA 损伤与内质网 (ER) 应激，另一种涉及表达表面活性蛋白的小鼠中低剂量博莱霉素C 突变与患者肺纤维化相关，第三个突变涉及赫曼斯基普德拉克综合征遗传模型中 ER 和溶酶体应激的诱导。我们还将评估每种抑制剂对从人类细胞和组织核心获得的正常肺部和 IPF 患者的小鼠 AECII 和人类 AECII 的有效性。我们还将利用应激的 AECII 和 BAL 以及来自纵向队列核心的血液样本来评估我们发现的由 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，我们期望确定在 PPG 第二阶段临床试验中测试的药物，以及快速监测这些化合物对患者有效性的策略。