Modeling and mechanistic investigation of a novel dry AMD mouse model with CLIC4 deleted in RPE

RPE 中删除 CLIC4 的新型干 AMD 小鼠模型的建模和机制研究

基本信息

批准号：
10279736
负责人：
CHING-HWA SUNG
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279736
关键词：
3-Dimensional Address Age related macular degeneration Animal Model Apolipoprotein E Basic Science Blindness Bruch&apos s basal membrane structure CLIC4 gene Cellular biology Complex Comprehension Coupling Deposition Disease Disease Progression Docosahexaenoic Acids Drusen Elderly Electron Microscopy Environmental Risk Factor Etiology Exhibits Financial compensation Functional disorder Genetic Genetic Risk Goals Histopathology Homeostasis Human Image Impairment In Vitro Investigation Knock-out Knockout Mice Knowledge Learning Lipids Lipoproteins Mass Spectrum Analysis Mediating Membrane Microdomains Metabolism Modeling Mus Nonexudative age-related macular degeneration Outcome Outcome Study Oxidation-Reduction Pathologic Peroxides Phenotype Phospholipids Photoreceptors Play Polyunsaturated Fatty Acids Population Primary Lesion Proteins Regulation Research Role Signal Pathway Site Sphingolipids Structure of retinal pigment epithelium Sum Techniques Technology Testing TimeLine Triglycerides Vision Visual impairment base effective therapy geographic atrophy in vivo interdisciplinary approach lipid metabolism lipid transfer protein lipidomics liquid chromatography mass spectrometry mouse model new therapeutic target novel peroxidation trafficking transcriptome

项目摘要

SUMMARY Aged-related macular degeneration (AMD) is a complex disease and the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen deposits are the silent hallmark of dry AMD. The retinal pigment epithelium (RPE) is likely to be the primary lesion site of AMD. Lacking an AMD mouse model is a roadblock to advance this research field. Recently we showed that RPE-specific CLIC4 knockout (KO) mice develop a full spectrum of AMD-like pathophysiology, including the impaired visual function, the drusen-like deposition, and severe RPE cell loss. CLIC4 is a redox-sensing pleiotropic protein. Our characterizations showed CLIC4 deficiency alters a myriad of signaling pathways that are required for maintaining RPE homeostasis. In particular, CLIC4-KO RPE cells had profound lipid dysregulation. We proposed two specific aims to understand CLIC4's role in coupling several aspects of the lipid homeostasis-metabolism, storage, and transport. We will investigate the lipid homeostasis of the RPE in the context of cell biology. The overarching goal is to learn how integrated outcomes as a consequence of loss-of-CLIC4 present the AMD-like pathophysiology. We will investigate CLIC4’s role in the phospholipid (Aim1) and sphingolipid (Aim2) homeostasis of RPE (Aim1) in the aspects of the lipid metabolism, storage, and transport. We will use interdisciplinary approaches and state-of-the-art techniques (e.g., Imaging Mass Spectrometry- LC/MS-MS lipidomics, transcriptomes, 3D electron microscopy) to studies these questions both in vivo and in vitro. The obtained information will significantly advance our comprehension of the basic science of the RPE and AMD etiology. They also have a strong potential for discovering new drug targets to treat AMD.

概括与老年相关的黄斑变性（AMD）是一种复杂的疾病，是老年人的失明沉积物是视网膜色素上皮（RPE）的静音标志 AMD的主要病变部位。研究领域。类似AMD的病理生理学的光谱，包括视觉功能受损的功能，drusen样沉积和严重的RPE细胞损失表征表明Clic4缺乏改变了无数的信号通路维持RPE稳态所需失调。我们支撑了两个特定的目的脂质稳态，储存和运输的方面。在细胞生物学的背景下，RPE的稳态。综合结局作为CLIC4丧失的结局，呈现出AMD样的病理生理学。我们将研究CLIC4在磷脂（AIM1）和鞘脂（AIM2）稳态中的作用 RPE（AIM1）在脂质代谢，储存和运输方面跨性别和最新技术（例如，成像质谱 - LC/MS-MS脂质组学，转录，3D电子显微镜）研究了这些问题体内和体外的信息将大大提高我们对 RPE和AMD病因的基础科学也有强大的潜力新药物的靶标可以信任AMD。