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Targeting lysosome/RPE heterogeneity in AMD pathobiology as a novel therapy

针对 AMD 病理学中的溶酶体/RPE 异质性作为一种新疗法

基本信息

批准号：
10636943
负责人：
James T Handa
金额：
$ 60.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636943
关键词：
Actins Address Affect Age Age related macular degeneration Aging Antioxidants Autoantibodies Automobile Driving Autophagocytosis Autophagosome Behavior Biogenesis Blindness Cell Death Cell Nucleus Cell physiology Cells Cessation of life Characteristics Chronic Crystallins Cytoskeletal Modeling Cytosol Defect Disease Dose E-Cadherin Elderly Endosomes Environment Epidermal Growth Factor Receptor Epithelium Exhibits Eye Functional disorder Gene Activation Genetically Engineered Mouse Health Heterogeneity Homeostasis Human Impairment Injections Knockout Mice Laboratories Link Lysosomes Mesenchymal Messenger RNA Micronutrients Minority Molecular Analysis Nonexudative age-related macular degeneration Nuclear Oxidative Stress Pathogenesis Pathologic Pathology Patients Phagocytosis Phenotype Prevention Process Proteins Receptor Signaling Rejuvenation Resistance Retina Rodent Model Stains Stress Structure of retinal pigment epithelium Testing Therapeutic Agents Time Tissues Vascular Diseases Vimentin Vision Work activating transcription factor adeno-associated viral vector age related aging population bafilomycin A1 bevacizumab cigarette smoke conditional knockout epithelial to mesenchymal transition gene network gene therapy in vivo induced pluripotent stem cell mouse model mutant neovascular novel novel therapeutics pre-clinical preservation prevent promoter response targeted treatment therapeutic target transcription factor transcriptome

项目摘要

SUMMARY: Vision loss from age-related macular degeneration (AMD) is a major, expanding problem due to the aging population. While treatment is available for intermediate AMD and the advanced wet form, no prevention or treatment is available for early AMD. While cellular heterogeneity can help tissue adapt to stress, degenerative heterogeneity from aging is associated with disease. The current perspective is that RPE (retinal pigmented epithelium) degeneration is a central, chronic process that inevitably leads to cell death. Thus, prior studies have focused on the impact of RPE cell death on AMD pathobiology. However, a subset of RPE cells exhibit features of epithelial-mesenchymal transition (EMT), an adaptive process that allows cells to survive a harsh environment. RPE heterogeneity has been recognized for some time, but the impact of disease driving cell subsets on AMD pathogenesis has not been considered. Lysosomal dysfunction is clearly involved in several age-related diseases including AMD, but the impact of heterogeneity of lysosomal impairment, which can cause disease, on RPE cellular function or heterogeneity has not been considered. This proposal is a departure from the norm because it proposes that RPE heterogeneity including a subset of cells with EMT in early AMD is initiated by heterogeneity of lysosomal clearance defects. RPE in EMT are resistant to death, and thus, could drive AMD pathobiology for an extended period. On the other hand, since EMT can be reversed, RPE in EMT are a compelling treatment target because its vision preserving functions can be restored. Lysosomal function and autophagy are modulated by the master regulator transcription factor EB (TFEB). Our laboratory has demonstrated reduced nuclear TFEB staining in the RPE of early AMD globes compared to age-matched controls, thus identifying TFEB as a potential therapeutic target for AMD. Given the possibility that heterogeneity of lysosomal dysfunction drives RPE heterogeneity, from EMT to degeneration, the objective of this proposal is to determine the impact of restoring lysosomal function and autophagy on the AMD-associated RPE heterogeneity in our validated Cryba1 cKO rodent model of lysosomal impairment that develops a dry AMD-like phenotype, and in human-iPSC derived RPE cells. The central hypothesis of “rejuvenating lysosomal and autophagic function by activating TFEB will maintain RPE cell function and prevent pathologic RPE heterogeneity including EMT, in early AMD” will be addressed with the following aims: Aim 1: Test the extent that TFEB activation rejuvenates lysosomal/autophagy function, and modulates RPE heterogeneity and RPE cell health. Aim 2: Test the degree that TFEB activation in the RPE of Cryba1 cKO mice rescues its AMD-like phenotype. Aim 3: Test the degree that lysosomal heterogeneity leads to RPE heterogeneity in AMD. Successful completion of this proposal will establish the novel concept of lysosome/autophagy dysfunction as a key driver of RPE heterogeneity in early AMD and identify TFEB as a novel therapeutic agent.

摘要：老年性黄斑变性（AMD）导致的视力丧失是一个主要的、日益严重的问题

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thermal Shift Assay in Ferroptosis.

铁死亡中的热位移测定。

DOI：
10.1007/978-1-0716-3433-2_16
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Bammidi,Sridhar;Hose,Stacey;Handa,JamesT;Sinha,Debasish;Ghosh,Sayan
通讯作者：
Ghosh,Sayan

Microglia-Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model.

DOI：
10.3390/cells11223535
发表时间：
2022-11-09
期刊：
Cells
影响因子：
6
作者：
通讯作者：

A Novel Method of Mouse RPE Explant Culture and Effective Introduction of Transgenes Using Adenoviral Transduction for In Vitro Studies in AMD.

DOI：
10.3390/ijms222111979
发表时间：
2021-11-05
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Shang P;Stepicheva NA;Liu H;Chowdhury O;Franks J;Sun M;Hose S;Ghosh S;Yazdankhah M;Strizhakova A;Stolz DB;Zigler JS Jr;Sinha D
通讯作者：
Sinha D