Defining oxidative stress induced changes in RPE that control RPE and photoreceptor degeneration

定义氧化应激诱导的 RPE 变化，控制 RPE 和光感受器变性

• 批准号: 10315588
• 负责人: Manas R Biswal
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315588
• 关键词: Affect; Affinity Chromatography; Age; Age related macular degeneration; Atrophic; Binding; Biochemical; Biological Assay; Blindness; Bruch' s basal membrane structure; CASP1 gene; CCL2 gene; Cathepsins B; Cell Culture Techniques; Cell Surface Proteins; Cell surface; Cessation of life; Choroidal Neovascularization; Chronic; Confocal Microscopy; Data Set; Defect; Deposition; Development; Disease; Disease Progression; ERCC2 gene; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Event; Exudative age-related macular degeneration; Eye; Fluorescein-5-isothiocyanate; Foundations; Functional disorder; Gene Expression; Genes; Goals; Health; Immunofluorescence Immunologic; Immunohistochemistry; Impairment; In Vitro; Individual; Inflammasome; Inflammatory; Injury; Interleukin-1 alpha; Interleukin-18; Interleukin-6; Label; Lasers; LysoTracker; Lysosomes; Magic; Maintenance; Measures; Membrane Proteins; Mitochondria; Modeling; Molecular; Mus; Nonexudative age-related macular degeneration; Ovalbumin; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Phenotype; Photoreceptors; Play; Process; Protein Isoforms; Proteins; Proteomics; Public Health; Reactive Oxygen Species; Reporting; Research; Retina; Retinal Degeneration; Retinal Photoreceptors; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Rhodopsin; Role; SOD2 gene; Scanning; Signal Pathway; Site; Stains; Streptavidin; Structure; Structure of retinal pigment epithelium; System; Systems Biology; Testing; Time; Training; Vacuole; Western Blotting; age related; base; career development; cytokine; differential expression; effective therapy; epithelial injury; geographic atrophy; improved; in vivo; loss of function; macula; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; photoreceptor cell outer segment; photoreceptor degeneration; prevent; recombinase-mediated cassette exchange; therapy development; tool; transcriptome sequencing

Summary Age-related macular degeneration (AMD) causes vision loss among many older individuals, and the retinal pigment epithelium (RPE) is thought to be a critical site of injury. Vision loss in AMD occurs due to photoreceptor degeneration and/or choroidal neovascularization. Geographic atrophy (GA), the advanced form of dry AMD, is characterized by the breakdown of RPE, choriocapillaris, and photoreceptors, especially in the macula. Lack of clear understanding of the molecular mechanisms of GA hinders the development of therapy. For lifelong maintenance of photoreceptors, RPE cells play an essential role in phagocytosis and degradation of tips shed from photoreceptor outer segments (POS). Photoreceptors and RPE cells are susceptible to injury from mitochondrial oxidative stress. The central goal of the project is to understand how photoreceptor degeneration occurs in GA. I hypothesize that oxidative stress impairs phagocytosis and lysosome function and ultimately activates inflammatory processes in RPE that stimulate geographic atrophy. I will test my hypothesis in RPE cell culture and in a new mouse model of age dependent RPE atrophy that was recently developed in our lab. In this model we used the cre/lox system to generate an RPE-specific deletion of Sod2, the mitochondrial gene for manganese superoxide dismutase (MnSOD). These mice develop a normal RPE but overtime the RPE has elevated oxidative stress resulting in phenotypic changes that are commonly observed in AMD, including RPE injury, loss of function and subsequent retinal degeneration. In the context of GA, I have following aims: (1) To characterize the impact of oxidative stress on phagocytosis, lysosomal function and inflammasome activation in RPE; (2) Identify molecular changes in RPE under oxidative stress. These studies will illuminate signaling pathways that drive photoreceptor and RPE loss and will provide a foundation to develop new therapeutic targets to prevent disease progression in AMD.

概括 年龄相关性黄斑变性（AMD）导致许多老年人视力丧失，并且 视网膜色素上皮（RPE）被认为是损伤的关键部位。 AMD 视力丧失 由于光感受器变性和/或脉络膜新生血管形成而发生。地理 萎缩 (GA) 是干性 AMD 的高级形式，其特征是 RPE 崩溃， 脉络膜毛细血管和光感受器，特别是在黄斑中。缺乏清晰的认识 GA的分子机制阻碍了治疗的发展。终身维护 光感受器、RPE细胞在尖端脱落的吞噬和降解中发挥重要作用 来自光感受器外节（POS）。感光细胞和视网膜色素上皮细胞容易受到损伤 来自线粒体氧化应激。该项目的中心目标是了解如何 GA 中发生光感受器变性。我假设氧化应激会损害 吞噬作用和溶酶体功能，并最终激活 RPE 中的炎症过程， 刺激地理萎缩。我将在 RPE 细胞培养物和新小鼠中检验我的假设 我们实验室最近开发了年龄依赖性 RPE 萎缩模型。在这个模型中我们 使用 cre/lox 系统生成 Sod2 的 RPE 特异性删除，Sod2 是线粒体基因 锰超氧化物歧化酶（MnSOD）。这些小鼠出现正常的 RPE，但随着时间的推移 RPE 具有升高的氧化应激，导致常见的表型变化 AMD 中观察到的症状包括 RPE 损伤、功能丧失和随后的视网膜变性。在 在 GA 的背景下，我有以下目标：（1）表征氧化应激对 RPE 中的吞噬作用、溶酶体功能和炎症小体激活； (2) 识别分子 氧化应激下 RPE 的变化。这些研究将阐明驱动信号通路 光感受器和 RPE 损失，将为开发新的治疗靶点奠定基础 预防 AMD 疾病进展。

项目成果

Single-Atom Nanozyme for Wound Antibacterial Applications

用于伤口抗菌应用的单原子纳米酶

• 发表时间: 2024-09-13
• 作者: Kelong Fan;Xiyun Yan;Huiyu Liu
• 通讯作者: Huiyu Liu

Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases.

碳点纳米颗粒：探索基因传递在眼科疾病中的潜在用途。

• 发表时间: 2021-04-06
• 作者: Biswal, Manas R;Bhatia, Sofia
• 通讯作者: Bhatia, Sofia

Impact of age and sex on hyperoxia-induced cardiovascular pathophysiology.

年龄和性别对高氧诱导的心血管病理生理学的影响。

• 发表时间: 2022-12
• 影响因子: 5.3
• 作者: Vichare, Riddhi;Saleem, Faizan;Mansour, Hussein;Bojkovic, Katarina;Cheng, Feng;Biswal, Manas;Panguluri, Siva Kumar
• 通讯作者: Panguluri, Siva Kumar