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Crosstalk between chronic ER stress and mitophagy for the treatment of POAG

慢性 ER 应激与线粒体自噬治疗 POAG 之间的串扰

基本信息

批准号：
10445174
负责人：
Gulab Zode
金额：
$ 37万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445174
关键词：
Autophagocytosis Autopsy Biological Assay Blindness Cell Death Cell model Cell physiology Cells Cessation of life Chronic Deposition Disease Endoplasmic Reticulum Enhancers Exhibits Extracellular Matrix Eye Eyedrops Fibrosis Functional disorder Funding Genetic Genus Hippocampus Glaucoma Glucocorticoids Goals Health Homeostasis Human Impairment In Vitro Link Lysosomes Membrane Metformin Mitochondria Molecular Mus Nerve Degeneration Normal tissue morphology Ocular Hypertension Organelles Pathologic Pathology Pathway interactions Pharmacology Physiologic Intraocular Pressure Play Primary Open Angle Glaucoma Proteins Reactive Oxygen Species Reporter Role Stress Time Tissues Trabecular meshwork structure Transmission Electron Microscopy Work endoplasmic reticulum stress improved in vivo in vivo Model insight mitochondrial dysfunction mouse model novel prevent transcription factor treatment strategy

项目摘要

Abstract Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Elevated intraocular pressure (IOP) due to dysfunction of trabecular meshwork (TM) tissue is a hallmark of POAG. However, the pathological mechanisms leading to TM dysfunction and IOP elevation are poorly understood. Our recent studies have shown that chronic endoplasmic reticulum (ER) stress is associated with the pathophysiology of glaucomatous TM damage and IOP elevation. However, the exact mechanisms of TM cell dysfunction/loss are not completely understood. The ER and mitochondria communicate constantly via mitochondria-associated ER membranes (MAMs) to regulate vital cellular functions including autophagy. Autophagy degrades long-lived proteins and damaged organelles including mitochondria (known as mitophagy) via lysosomes. Impaired mitophagy is known to cause abnormal accumulation of damaged mitochondria resulting into cell death. In our preliminary studies, primary human TM cells exhibited an abundant mitochondria and MAMs. Interestingly, human primary TM cells and TM tissues from POAG donor eyes demonstrated increased accumulation of mitochondria. Moreover, chronic ER stress-induced transcriptional factors, ATF4 and CHOP led to increased reactive oxygen species and impaired mitophagy in primary human TM cells. Our overall goals are to define the role of MAMs and impaired mitophagy in TM dysfunction and IOP elevation in POAG and to further target these pathways for the treatment of glaucoma. We hypothesize that chronic ER stress induces impaired mitophagy and mitochondrial dysfunction, leading to TM dysfunction/loss and IOP elevation in POAG. We will determine whether impaired mitophagy and mitochondrial dysfunction are associated with TM dysfunction and IOP elevation in human and mouse glaucoma (Aim 1). We will further determine whether chronic ER stress induces impaired mitophagy and mitochondrial dysfunction, leading to TM dysfunction/loss and IOP elevation (Aim 2). Finally, we will perform proof-of-principle studies exploring whether the mitophagy enhancers improve outflow facility and reduce elevated IOP in mouse models of glaucoma (Aim 3). We will utilize human primary TM cells and post-mortem TM tissues from normal and glaucoma donor eyes, mouse models of glaucoma and mitophagy flux reporter mouse model (mito-qc) as well as transmission electron microscopy (TEM) and the Seahorse assays to determine the role of MAMs, mitophagy and mitochondrial dysfunction in TM function and IOP homeostasis. The successful completion of the proposed studies will provide novel crosstalk between ER stress and mitophagy and target the pathological mechanisms for the treatment of general POAG.