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（请参阅说明）：特发性肺纤维化（IPF）的病因和发病机理的新兴理论基于慢性损伤，异常修复和II型肺泡上皮细胞（AECII）的凋亡的概念，这是分泌表面活性剂的专门肺细胞。由于AECII是含有高活性内质网（ER）细胞器的专业分泌细胞，因此我们假设随着蛋白质折叠能力变得疲惫，上游众多的上游侮辱可能会产生ER应力。一种称为展开的蛋白质反应（UPR）的信号传导途径可适应ER应激，但如果应力不可用，可能会矛盾地引起凋亡。我们学会了通过开发的新型小分子UPR调节剂来防止UPR的关键破坏性输出。在此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）来测试新出现的假设，即ER应激诱导的AECII凋亡对于通过改善凋亡过程的发展和这种死亡疾病进展的潜在改善而对IPF的发展至关重要。 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 Hermansky Pudlak综合征的遗传模型中的溶物质体应激。我们还将评估从正常肺和从人类细胞和组织核心获得的IPF患者的每种抑制剂对鼠AECII和人AECII的有效性。我们还将利用纵向队列核心的应力AECIIS和BAL和BAL和血液样本来评估我们发现由UPR调节的胶片效用，作为该途径的机械学信息性生物标志物。基于这项工作，我们希望在该PPG的第二阶段中鉴定出在临床试验中测试的药物，并迅速监测这些化合物在患者中的有效性。