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Innate immune system regulation of retinal regeneration

先天免疫系统对视网膜再生的调节

基本信息

批准号：
10707048
负责人：
JEFFREY MUMM
金额：
$ 44.1万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707048
关键词：
Ablation Acute Address Adult Bioinformatics CRISPR/Cas technology Cell Death Cells Cone Data Development Disease Fatty acid glycerol esters Feedback Fishes Genes Genetic Genetic screening method Goals Histology Human Image Immune Immune system Immunosuppression In Vitro Injury Innate Immune System Kinetics Label Larva Link Mammals Methodology Methods Microglia Modeling Molecular Natural regeneration Nature Outcome Patients Photoreceptors Play Process Publishing Regenerative capacity Regulation Resources Retina Retinal Cone Retinal Ganglion Cells Role Shapes Specificity System Testing Therapeutic Time Titrations Transgenic Organisms Vision Vision Disorders Zebrafish cell type experimental study gene network glial activation immunoregulation improved in vivo in vivo imaging insight mathematical model novel progenitor programs regeneration potential regenerative regenerative therapy repaired retinal neuron retinal progenitor cell retinal regeneration sight restoration stem cell niche stem cell proliferation stem cells transcriptomics

项目摘要

PROJECT SUMMARY Degenerative vision disorders are caused by the loss of retinal cells. In zebrafish, retinal Müller glial (MG) act as stem cells, generating MG-derived progenitor cells (MGPCs) which replace lost retinal cells. Mammalian MG/MGPCs can also produce new retinal neurons, however, proliferative capacity is limited and disease- relevant cell types (e.g., photoreceptors) are rarely generated. Our goal is to understand why the regenerative potential of MG/MGPCs are limited in mammals in comparison to a regenerative species (i.e. zebrafish). In zebrafish, widespread retinal cell loss triggers “developmental” regeneration, producing all major retinal cell classes. Conversely, selective retinal cell loss results in a “fate-biased” process where MGPCs give rise to the lost cell type. How MG sense the extent of loss, however, is unknown. As the immune system plays critical roles during retinal regeneration, we examined the impact of microglia reactivity on MG activation in zebrafish. We observed that microglia are required for MG stem cell activation and that immunosuppression can inhibit or enhance regeneration kinetics depending on the treatment timing. We hypothesize that microglia reactivity levels scale to the extent, duration, and/or specificity of retinal cell loss in order to coordinate MG activation, MGPC proliferation rates and fat decisions to the type of injury incurred. To test our hypothesis, here we propose to combine an improved targeted cell ablation system enabling titratable, sustainable, and selective retinal cell loss with resources/methods for labeling of immune cell types, intravital timelapse imaging, lineage tracing, and single cell transcriptomics. Specifically we will define how the extent (Aim 1), the duration (Aim 2) and specificity (Aim 3) of cone photoreceptor or retinal ganglion cell loss impact immune cell reactivity and retinal regeneration. These experiments will serve to define roles specific immune cell subtypes play in shaping MGPC proliferation and cell fates during regeneration in zebrafish.

项目总结