Rod photoreceptor regeneration in a zebrafish model of Retinitis Pigmentosa.

摘要： 遗传性视网膜变性疾病的细胞标志，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。随着退化开始在早期的年龄，许多 患有RP的患者在成年早期就失明。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变性疾病， 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）具有在视网膜损伤或疾病后再生神经元的显著能力，使它们能够再生神经元。 再生研究的合适模式生物。目前对Zf的研究表明，在检测到 视网膜损伤后，M-111 ller胶质细胞（MGCs）被重编程以重新进入细胞周期，不对称分裂， 产生多能祖细胞。这些新形成的祖细胞迅速增殖并重新分化 来替换失去的视网膜细胞一些基因、途径和转录因子已被证明在其中发挥作用 在重编程MGCs，诱导祖细胞增殖，并将这些细胞分化为功能性内分泌细胞中， 视网膜神经元;然而，基因在空间和时间上共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。本研究的目的是了解 Zf中视杆细胞光感受器的再生机制，并确定关键的主调控基因， 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， 负责视杆细胞再生。本提案的目标1将评估候选人的角色 调节基因和转录因子在这些祖细胞分化成视杆细胞中的作用。 目标2将评估祖细胞形成视杆细胞的谱系轨迹，并确定何时以及如何形成视杆细胞。 形成祖细胞。在这个项目成功完成后，我将确定一套 转录因子需要诱导成年Zf视杆细胞再生。这个项目的最终目标 是为患有视网膜变性疾病的盲人患者提供恢复视力所需的靶点， RP，以便他们可以提高生活质量。

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.