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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结