Promoting RPE repair through modulation of Hippo signaling

通过调节 Hippo 信号传导促进 RPE 修复

• 批准号: 10385789
• 负责人: SABINE FUHRMANN
• 金额: $ 20.62万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385789
• 关键词: Adult; Age related macular degeneration; Aging; Animal Model; Atrophic; Blindness; Cell Death; Cell Density; Cell physiology; Cells; Chemicals; Choroid; Chronic Disease; Clinical; Critical Pathways; Data; Development; Differentiation and Growth; Disease; Elderly; Epithelial; Eye; Eye diseases; Gene Expression Profiling; Genetic; Goals; Growth; Heterogeneity; Histologic; Homeostasis; Human; Hypertrophy; Injury; Investigation; Knowledge; Label; Macular degeneration; Metabolism; Modeling; Molecular; Mus; Natural regeneration; Neural Retina; Neurobiology; Neurofibromin 2; Nonexudative age-related macular degeneration; Nuclear; Pathway interactions; Peripheral; Photoreceptors; Population; Production; Property; Regenerative Medicine; Regenerative capacity; Regenerative response; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; Therapeutic; Tissues; Translating; beta catenin; epithelial injury; epithelial repair; epithelium regeneration; functional improvement; genetic predictors; healing; improved; in vivo; insight; monolayer; novel; novel therapeutics; oxidative damage; photoreceptor degeneration; programs; regeneration potential; regenerative; regenerative repair; repaired; retinal damage; self-renewal; sight restoration; single-cell RNA sequencing; sodium iodate; stem cells

The  retinal  pigment  epithelium  (RPE)  maintains  tissue  homeostasis  through  long-­term  survival,  with  little  evidence of de novo cell production. Due to continued growth of the eye and aging, cell density decreases and  RPE  cells  generally  undergo  hypertrophy.  Degeneration  of  the  central  RPE  causes  the  progressive  chronic  disease  age-­related  macular  degeneration  (AMD),  the  leading  cause  of  irreversible  vision  loss  in  the  elderly  population. Besides some protective strategies, no effective cure for AMD is currently available. Recent studies  revealed that substantial cell heterogeneity may be a feature that exists throughout the RPE. Importantly, certain  subsets of this heterogeneous RPE cell population may contain distinct properties contributing to regeneration,  with an intrinsic capacity for self-­renewal. We and others identified signaling pathways critical for developmental  RPE  growth  and  differentiation,  specifically  the  Hippo  and  Wnt  pathways.  Here  we  propose  to  explore  how  genetic modulation of such signaling pathways can stimulate regenerative repair in the mature mammalian RPE  and  to  identify  RPE  subpopulations  with  regenerative potential.  Our  studies  will  provide  insight  into  potential  novel regulators stimulating an intrinsic, regenerative response in the mature RPE. Identifying candidate targets  for  clinical  therapy  is  a  critical  step  forward  for  treatment  of  RPE-­related  diseases  with  currently  very  limited  therapeutic potential, such as atrophic AMD.

视网膜色素上皮（RPE）通过长期存活维持组织的稳态，但很少