Partial epigenetic reprogramming of retinal pigment cells in age-related degeneration, dysfunction, and injury

视网膜色素细胞在年龄相关变性、功能障碍和损伤中的部分表观遗传重编程

• 批准号: 10644270
• 负责人: Zhengping Hu
• 金额: $ 11.4万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644270
• 关键词: Adult; Age; Age related macular degeneration; Aging; Atrophic; Blindness; Cell Aging; Cell Death; Cell Reprogramming; Cell physiology; Cells; Cellular Morphology; Cellular Stress; Cholesterol; Complement; Complement Activation; Crush Injury; DNA; DNA Methylation; Data; Deposition; Development; Diet; Doxycycline; Dryness; Elderly; Electrophysiology (science); Electroretinography; Epigenetic Process; Exudative age-related macular degeneration; Eye diseases; Fatty acid glycerol esters; Functional disorder; Gene Delivery; Gene Modified; Glaucoma; Heterozygote; Human; In Vitro; Injury; Investigation; Knowledge; Mediating; Mentors; Modeling; Modification; Molecular; Morphology; Mus; Neural Retina; Nitrogen; Nonexudative age-related macular degeneration; Optic Nerve; Oxidative Stress; Oxygen; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phase; Photoreceptors; Play; Population; Process; Regenerative capacity; Reporting; Research Personnel; Resistance; Retina; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinal Pigments; Risk; Risk Factors; Role; Safety; Serum; Signal Pathway; Site; Structure of retinal pigment epithelium; Testing; Therapeutic; Tobacco; Tobacco smoking behavior; Training; Transmission Electron Microscopy; Vision; Work; age related; aged; axon regeneration; bevacizumab; career; cell injury; cigarette smoking; comparative; epigenome; epithelial injury; high risk; improved; in vivo; in vivo Model; in vivo regeneration; induced pluripotent stem cell; insight; juvenile animal; methylation pattern; mouse model; neovascular; novel therapeutic intervention; oxidized low density lipoprotein; pluripotency; prevent; programs; response; senescence; skills; sodium iodate; stem cell differentiation; transcriptome

PROJECT SUMMARY Retinal pigment epithelial (RPE) cell dysfunction and damage are hallmarks of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. While anti-VEGF has revolutionized the management of wet or exudative AMD, there is currently no treatment available for non-exudative AMD. Aging is the major risk factor for RPE degeneration and the development of AMD. During aging, epigenetic changes disrupt "youthful" DNA methylation patterns, leading to cellular dysfunction and senescence. Partial epigenetic reprogramming via ectopic induction of three Yamanaka factors, Oct4, Sox2, Klf4 (OSK), in retinal ganglion cells was recently reported to reprogram and reverse epigenetic age, leading to vision improvement in aged mice as well as in a mouse glaucoma model. I propose to test the hypothesis that partial epigenetic reprogramming can rescue age-related RPE cell degeneration and function in vivo, prevent RPE cell injury induced by a range of insults in vitro, and inhibit the formation of AMD-like pathologies in a mouse model with the following aims. (i) To determine whether OSK-mediated epigenetic reprogramming can restore RPE morphology and function in aged mice, I will examine the visual function and RPE morphology in aged mice with and without OSK induction by optomotor, ERG, RPE flatmount, and transmission electron microscopy. In addition, I will compare the transcriptomes and epigenomes of RPE from aged mice with and without OSK induction to assess the effect of OSK expression. (ii) To test the ability of OSK-induction in rescuing primary human RPE cells from morphologic and functional changes, as well as cell death following various AMD- associated insults in vitro, including oxidative stress, ox-LDL, and cigarette smoking extract. I will also examine the effect of OSK-induction in iPSC-RPE cells derived from high-risk and low-risk donors with AMD. (iii) Examine the role of OSK induction in NaIO3-treated mice, a short-term injury model that induces regional RPE atrophy, and in RPE specific aged Cfh heterozygous (Cfh+/-) mice fed with a high fat, high cholesterol diet, which have pathological changes mimicking early dry AMD. The results of these investigations will reveal the efficacy and viability of epigenetic reprogramming as a therapeutic strategy for RPE regeneration in vivo. My mentoring panel and the proposed training plan will equip me with new knowledge and skills to study age- related retinal diseases and will catalyze my transition to a career as an independent investigator.

项目总结