Cells and genes that govern inflammation in the subretinal space

控制视网膜下腔炎症的细胞和基因

• 批准号: 10666747
• 负责人: Peter F Hitchcock
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666747
• 关键词: Ablation; Animal Model; Bioinformatics; Blindness; Cause of Death; Cell Cycle Kinetics; Cell Death; Cell physiology; Cells; Cessation of life; Data; Disease; Foundations; Future; Genes; Genetic Transcription; Goals; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Mediating; Mediator; Microglia; Mission; Modeling; Molecular; Motivation; Muller' s cell; Mutation; Natural Immunity; Natural regeneration; Nervous System; Neurons; Outcome; Pathway interactions; Photoreceptors; Physiology; Play; Population; Proliferating; Research; Retina; Retinal Cone; Retinal Photoreceptors; Role; Site; Source; Tissues; Vision; Work; Zebrafish; age related; cell type; cold blooded vertebrate; design; differential expression; driving force; inflammatory milieu; insight; migration; nerve stem cell; neural circuit; neuron regeneration; novel; progenitor; programs; regenerative biology; repaired; response; response to injury; retinal neuron; retinal regeneration; stem; stem cells; transcriptome; transcriptome sequencing; transcriptomics

Abstract Injuries or diseases that kill retinal neurons or photoreceptors block vision at it source. The inability to repair the retina is a hallmark of the human nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The objective of this project is to undertake novel exploratory studies that will investigate new concepts and characterize newly-identified cell types that are hypothesized to play key roles during the death and regeneration of photoreceptors in the vertebrate retina. This work will extend projects in our lab toward new directions. This program of research utilizes the zebrafish retina, the only vertebrate CNS tissue in which endogenous cells can regenerate a single neuronal type, which integrates into existing synaptic circuits, or regenerate all cell types that can completely restore the original tissue. Two Specific Aims are proposed, each designed to reveal important insights into the cellular and molecular mechanisms that govern inflammation in subretinal space during photoreceptor death and regeneration. Specific Aim 1 will explore the role the RPE plays in establishing the inflammatory mileau within the sub-retinal space during the selective death of cone photoreceptors. Specific Aim 2 will establish the transcriptomic signature of a newly-identified population of subretinal microglia, which, like the RPE, have an exclusive relationship to photoreceptors. Determining how the inflammatory response governs photoreceptor regeneration will advance our knowledge of the molecular mechanisms that govern retinal stem and progenitor cells and may guide cell-based therapeis for treating retinal injuries and disease in humans.

抽象的 杀死视网膜神经元或光感受器的损伤或疾病会从根源上阻碍视力。这 无法修复视网膜是人类神经系统的一个标志；死亡的神经元并不是 被替换并且丢失的功能不会恢复。这种惨淡的结果是推动 主要从事神经干细胞及再生生物学领域的研究。该项目的目标 是进行新颖的探索性研究，调查新概念并表征 新鉴定的细胞类型被假设在死亡和死亡过程中发挥关键作用 脊椎动物视网膜中光感受器的再生。这项工作将扩展我们实验室的项目 走向新的方向。 该研究计划利用斑马鱼视网膜，这是唯一一种脊椎动物中枢神经系统组织 内源细胞可以再生单一神经元类型，该神经元类型整合到现有的突触中 电路，或再生所有可以完全恢复原始组织的细胞类型。 提出了两个具体目标，每个目标都旨在揭示对细胞的重要见解 以及光感受器期间视网膜下间隙控制炎症的分子机制 死亡和再生。具体目标 1 将探讨 RPE 在建立 视锥细胞选择性死亡过程中视网膜下腔内的炎症环境 光感受器。具体目标 2 将建立新鉴定的转录组签名 视网膜下小胶质细胞群，与 RPE 一样，与 光感受器。确定炎症反应如何控制光感受器 再生将增进我们对控制视网膜干的分子机制的了解 和祖细胞，并可能指导治疗视网膜损伤和疾病的细胞疗法 在人类中。