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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.

项目概述（见说明）：