Rod photoreceptor regeneration in a zebrafish model of Retinitis Pigmentosa.

摘要： 遗传性视网膜退行性疾病的细胞特征，如视网膜色素变性(RP)，是进行性的 光感受器的丧失，直到个体完全失明。由于退化在很小的时候就开始了，许多 RP患者在成年早期就会失明。仅在美国每年就有10万人受到影响 作为全球第二大遗传性视网膜退行性疾病，有必要在 以确定可以改善这些患者生活质量的治疗方法。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非凡的再生神经元的能力，使它们 适合再生研究的模式生物。ZF目前的研究表明，当检测到 视网膜损伤后，Mϋler胶质细胞(MGC)被重新编程，重新进入细胞周期，不对称分裂，并 培养出多能的祖细胞。这些新形成的祖细胞迅速增殖并重新分化 以替代丢失的视网膜细胞。一些基因、途径和转录因子已被证明起作用。 在对mGCs重新编程，诱导祖细胞增殖，并将这些细胞分化为有功能的内部 视网膜神经元；然而，基因在空间和时间上共同作用以再生的机制 慢性视网膜变性模型中的视杆细胞仍不清楚。这项研究的目的是了解 ZF中杆状感光器的再生机制及关键调控基因的筛选 他们的血统轨迹。我们的初步分析已经确定了一组视网膜祖细胞，据信是 负责杆状感光细胞的再生。本提案的目标1将评估候选人的角色 调控基因和转录因子在这些祖细胞分化为杆状感光细胞过程中的作用。 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 祖细胞就形成了。在这个项目成功完成后，我将确定一套 成体ZF中诱导杆状感光细胞再生所需的转录因子。这个项目的最终目标是 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 这样他们的生活质量可能会有所提高。

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.