Rod photoreceptor regeneration in a zebrafish model of Retinitis Pigmentosa.

色素性视网膜炎斑马鱼模型中杆状光感受器的再生。

• 批准号: 10607557
• 负责人: Eyad Shihabeddin
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-16 至 2026-01-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607557
• 关键词: Acute; Adult; Affect; Age; Automobile Driving; Blindness; CRISPR/Cas technology; Candidate Disease Gene; Cell Cycle; Cell Differentiation process; Cells; Chronic; Complete Blindness; Data; Data Set; Detection; Disease; E2F transcription factors; Fishes; Future; Gene Expression; Genes; Genetic; Goals; Incidence; Individual; Inherited; Injections; Injury; Knowledge; Mammals; Modeling; Molecular Biology Techniques; Molecular Profiling; Multipotent Stem Cells; Natural regeneration; Neuroglia; Neurons; Nuclear; Pathway Analysis; Pathway interactions; Patients; Persons; Photoreceptors; Play; Process; Proliferating; Pythons; Quality of life; Regenerative capacity; Regenerative research; Regulator Genes; Research; Retina; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Rhodopsin; Rod; Role; Source; System; Testing; Transgenic Organisms; United States; Vertebrate Photoreceptors; Vision; Work; Zebrafish; autosome; blind; candidate identification; cell type; experimental study; functional restoration; gene network; improved; interest; knock-down; model organism; mutant; neuron regeneration; overexpression; progenitor; promoter; regenerative therapy; retinal damage; retinal neuron; retinal progenitor cell; retinal rods; sight restoration; stem cell proliferation; stem cells; therapeutic target; transcription factor; transcriptomic profiling

Abstract: A cellular hallmark of inherited retinal degenerative diseases, such as Retinitis Pigmentosa (RP), is progressive loss of photoreceptors until the individual is completely blind. With degeneration starting at an early age, many patients with RP become blind early on in their adulthood. Affecting 100,000 people annually in the US alone and being the second most prominent genetic retinal degenerative disease worldwide, research is necessary in order to identify therapies that can improve the quality of life for these patients. Unlike mammalian models, Zebrafish (Zf) have a remarkable capacity to regenerate neurons following retinal injury or disease, making them a suitable model organism for regenerative studies. Current studies in Zf have indicated that upon detection of retinal insult, Mϋller glial cells (MGCs) are reprogrammed to re-enter the cell cycle, asymmetrically divide, and produce multi-potent progenitor cells. These newly formed progenitor cells rapidly proliferate and re-differentiate to replace lost retinal cells. Several genes, pathways, and transcriptional factors have been shown to play a role in reprogramming MGCs, inducing progenitor cell proliferation, and differentiating these cells into functional inner retinal neurons; however, the mechanisms by which genes work together spatially and temporally to regenerate rods in a model with chronic retinal degeneration remain unknown. The purpose of this study is to understand the regeneration mechanisms of rod photoreceptors in Zf and to identify the master regulatory genes crucial for their lineage trajectory. Our preliminary analyses have identified a group of retinal progenitor cells believed to be responsible for rod photoreceptor regeneration. Aim 1 of this proposal will assess the roles of candidate regulatory genes and transcription factors in the differentiation of these progenitor cells into rod photoreceptors. Aim 2 will assess the lineage trajectory of progenitor cells to form rod photoreceptors and identify when and how the progenitor cells are formed. Upon successful completion of this project, I will have identified the set of transcription factors needed to induce rod photoreceptor regeneration in adult Zf. The ultimate goal of this project is to provide the targets necessary to restore vision in blind patients with retinal degenerative diseases such as RP so that they may have an improved quality of life.

抽象的： 遗传性视网膜退行性疾病（例如色素性视网膜炎 (RP)）的细胞标志是进行性的 许多人在很小的时候就开始失去光感受器，直到完全失明。 RP 患者在成年早期就失明，仅在美国每年就有 100,000 人受到影响。 作为全球第二大遗传性视网膜退行性疾病，有必要进行研究 为了找到可以改善这些患者生活质量的疗法，与哺乳动物模型不同。 斑马鱼（Zf）在视网膜损伤或疾病后具有显着的神经元再生能力，使其成为 Zf 目前的研究表明，在检测到 时，它是一种适合再生研究的模型生物。 视网膜损伤后，米勒神经胶质细胞（MGC）被重新编程以重新进入细胞周期，不对称分裂，并且 产生多能祖细胞这些新形成的祖细胞快速增殖和再分化。 一些基因、途径和转录因子已被证明发挥了作用。 重编程 MGC、诱导祖细胞增殖以及将这些细胞分化为功能性内层细胞 然而，基因在空间和时间上协同工作以再生的机制 慢性视网膜变性模型中的视杆细胞仍然未知。这项研究的目的是了解。 Zf 中杆状光感受器的再生机制，并确定对 Zf 至关重要的主调控基因 我们的初步分析已经确定了一组被认为是视网膜祖细胞的细胞。 该提案的目标 1 将评估候选者的角色。 这些祖细胞分化为杆状光感受器的调节基因和转录因子。 目标 2 将评估祖细胞形成杆状光感受器的谱系轨迹，并确定何时以及如何形成 成功完成该项目后，我将确定祖细胞的集合。 诱导成人 Zf 视杆细胞再生所需的转录因子 该项目的最终目标。 是为患有视网膜退行性疾病的盲人患者提供恢复视力所需的目标，例如 RP 可以提高他们的生活质量。