Inflammatory Signaling and Regeneration in Zebrafish models of Retinal Degeneration

项目摘要 遗传性视网膜变性（IRD）是导致视网膜色素变性的进行性丧失的遗传性疾病。 光感受器和永久性视力丧失。野生型斑马鱼再生光感受器 通过将Müller胶质细胞重编程为产生视网膜祖细胞的干细胞样细胞， 这种再生过程未能发生在IRD的斑马鱼模型中。该提案将解决 这是一个尚未回答的关键问题，即为什么患有慢性炎症的斑马鱼突变体不能再生。 我们的初步数据表明，Notch途径抑制可以促进光感受器再生， 斑马鱼cep 290和bbs 2进行性变性模型及免疫抑制 防止感光细胞损失。这些结果提供了深入了解的途径，促进米勒胶质细胞， 依赖性再生和炎症在光感受器变性中的作用。我们的中央 一种假设是，在视网膜变性的斑马鱼模型中，慢性炎症导致视网膜变性的升高。 限制对急性损伤的再生反应的Notch和NF-kB信号传导。证据 文献和我们的初步数据严格证明，Müller胶质细胞中的Notch信号传导在以下方面不同： 对急性损伤或慢性变性的反应。了解促炎性疾病与 来自小神经胶质细胞的信号传导和Müller神经胶质细胞中的Notch信号传导以前没有得到解决。 此外，我们目前对炎症细胞因子如何通过NF-κ B信号传导的理解， 该途径仅在野生型动物的背景下进行了研究。拟议的研究将提供 对慢性疾病中小胶质细胞和Müller胶质细胞再生之间关系的重要见解。 我们将使用最先进的测序技术来识别Müller胶质细胞和小胶质细胞特异性 cep 290和bbs 2模型中基因表达的变化，以阐明 炎症和再生之间的联系我们还将鉴定和测试特定的配体-受体对 确定在斑马鱼变性突变体中维持Notch信号传导的机制， 确定刺激NF-kB信号传导的关键因素。理解支撑 在多种斑马鱼疾病模型中的视网膜再生将产生新的假设， 最终转化为人类视网膜退行性疾病。

Project Summary Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision. Wild-type zebrafish regenerate photoreceptors after acute injury by reprogramming Müller glia into stem-like cells that produce retinal progenitors. This regenerative process fails to occur in zebrafish models of IRDs. This proposal will address the critical unanswered question as to why zebrafish mutants with chronic inflammation fail to regenerate. Our preliminary data show that Notch pathway inhibition can promote photoreceptor regeneration in the zebrafish cep290 and bbs2 models of progressive degeneration and that immunosuppression prevents photoreceptor loss. These results offer insight into the pathways that promote Müller glia- dependent regeneration and the role of inflammation in photoreceptor degeneration. Our central hypothesis is that in zebrafish models of retinal degeneration, chronic inflammation results in elevated Notch and NF-kB signaling that restricts the regenerative response to acute injury. Evidence from the literature and our preliminary data rigorously demonstrate that Notch signaling in Müller glia differs in response to acute injury or chronic degeneration. Understanding the link between pro-inflammatory signaling from microglia and Notch signaling in Müller glia has not been previously addressed. Furthermore, our current understanding of how inflammatory cytokines signal through the NF-kB pathway has only been studied in the context of wild-type animals. The proposed studies will provide critical insight into the relationship between microglia and Müller glia regeneration in chronic disease. We will use state-of-the-art sequencing technologies to identify Müller glia- and microglia-specific changes in gene expression in cep290 and bbs2 models in order to elucidate the relationship between inflammation and regeneration. We will also identify and test specific ligand-receptor pairs to identify the mechanisms that maintain Notch signaling in the zebrafish degeneration mutants and identify key factors that stimulate NF-kB signaling. Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease models will generate novel hypotheses that can ultimately be translated into humans with retinal degenerative diseases.