Inflammatory Signaling and Regeneration in Zebrafish models of Retinal Degeneration

视网膜变性斑马鱼模型中的炎症信号传导和再生

• 批准号: 10751153
• 负责人: Brian D Perkins
• 金额: $ 54.15万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751153
• 关键词: 1 year old; ATAC-seq; Acute; Address; Animals; Blindness; CRISPR/Cas technology; Cell Cycle; Cell Death; Cells; Cessation of life; Chronic; Chronic Disease; Cone; Cytokine Signaling; Data; Disease; Disease model; Exhibits; Gene Expression; Genetic; Genetic Diseases; Gliosis; Goals; Human; IL6 gene; Immune response; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injury; Lesion; Ligands; Light; Link; Literature; Macrophage; Mammals; Methods; Microglia; Modeling; Molecular; Muller' s cell; NF-kappa B; NOTCH3 gene; Natural regeneration; Neurons; Pathway interactions; Phase; Photoreceptors; Process; Proliferating; Regenerative research; Regenerative response; Repression; Resolution; Retina; Retinal Degeneration; Retinal Diseases; Retinal Dystrophy; Retinitis Pigmentosa; Role; Signal Pathway; Signal Transduction; Source; TNF gene; Technology; Testing; Therapeutic; Time; Translating; Up-Regulation; Vision; Zebrafish; cell regeneration; ciliopathy; cytokine; epigenomics; gene regulatory network; human model; inherited retinal degeneration; insight; multiple omics; mutant; nerve stem cell; notch protein; novel; pharmacologic; photoreceptor degeneration; prevent; programs; receptor; regenerative; response; retinal neuron; retinal progenitor cell; retinal regeneration; single nucleus RNA-sequencing; stem cell proliferation; stem-like cell

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.

项目概要 遗传性视网膜变性（IRD）是导致视网膜逐渐丧失的遗传性疾病。 光感受器和永久性视力丧失。野生型斑马鱼再生光感受器 急性损伤后，通过将米勒神经胶质细胞重编程为产生视网膜祖细胞的干细胞样细胞。 这种再生过程在 IRD 的斑马鱼模型中无法发生。该提案将解决 关于为什么患有慢性炎症的斑马鱼突变体无法再生，这是一个尚未解答的关键问题。 我们的初步数据表明，Notch 通路抑制可以促进光感受器再生 斑马鱼 cep290 和 bbs2 进行性退化模型和免疫抑制 防止光感受器损失。这些结果提供了对促进穆勒胶质细胞的途径的深入了解 依赖性再生和炎症在光感受器变性中的作用。我们的中央 假设是，在视网膜变性的斑马鱼模型中，慢性炎症导致 Notch 和 NF-kB 信号传导限制对急性损伤的再生反应。证据来自 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有所不同： 对急性损伤或慢性退化的反应。了解促炎症之间的联系 来自小胶质细胞的信号传导和穆勒胶质细胞中的 Notch 信号传导此前尚未得到解决。 此外，我们目前对炎症细胞因子如何通过 NF-kB 发出信号的理解 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穆勒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穆勒胶质细胞和小胶质细胞特异性 cep290 和 bbs2 模型中基因表达的变化，以阐明其中的关系 介于炎症和再生之间。我们还将鉴定和测试特定的配体-受体对 确定斑马鱼退化突变体中维持 Notch 信号传导的机制 确定刺激 NF-kB 信号传导的关键因素。了解支撑机制 多种斑马鱼疾病模型中的视网膜再生将产生新的假设 最终被转化为患有视网膜退行性疾病的人类。