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Investigation of the neuroimmune axis in retinal regeneration.

视网膜再生中神经免疫轴的研究。

基本信息

批准号：
10554281
负责人：
Levi J. Todd
金额：
$ 12.01万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2022-02-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554281
关键词：
Ablation Adult Blindness Catalogs Cells Cessation of life Chick Collaborations Data Disease Engineering Equipment Faculty Fishes Flow Cytometry Functional Regeneration Gene Expression Genes Goals Heterogeneity Histone Deacetylase Inhibitor Human Immune Immune system Immunohistochemistry Individual Infiltration Inflammation Inflammatory Injury Interferons Invaded Investigation Knock-in Mouse Mediating Microglia Molecular Monitor Muller&apos s cell Mus N-Methylaspartate Natural regeneration Neural Retina Neurodegenerative Disorders Neuroimmune Neuroimmune system Neurons Pathway interactions Peripheral Population Heterogeneity Process Quality of life Regenerative capacity Regenerative response Reporting Research Research Personnel Retina Signal Transduction Testing Therapeutic Training Training Activity Transgenic Mice Trauma Universities Vertebrates Vision Washington Zebrafish cell type experimental study immune activation immunoregulation improved in vivo regeneration inflammatory milieu monocyte nerve stem cell neurogenesis neuroimmunology neuron loss neuron regeneration novel strategies overexpression pharmacologic prevent progenitor programs regeneration potential regenerative regenerative therapy repair strategy repaired response response to injury retinal damage retinal neuron retinal regeneration single-cell RNA sequencing transcription factor

项目摘要

Project Summary/Abstract Loss of vision has a devastating impact on an individual's quality of life. Most blinding diseases result from loss of neurons in the retina. A promising strategy to treat sight-threatening diseases, is to harness the regenerative potential of cells within the retina. Müller glia (MG), possess an extraordinary capacity in lower vertebrates to regenerate retinal neurons. However, in mammalian retinas, including humans, MG are unable to replace neurons lost to injury or disease. Recently, we have developed strategies to neurogenically reprogram MG in adult mice by overexpressing the transcription factor Ascl1 in MG. Remarkably, the treatment of Ascl1 overexpression, combined with NMDA-induced retinal damage and histone deacetylase (HDAC) inhibition, causes MG to regenerate functional neurons in the adult mammalian retina. While this is significant progress towards realizing the therapeutic potential of MG, only a subset of MG successfully reprogram into neurogenic progenitors while another subset of MG express genes associated with inflammatory processes. We hypothesized that the inflammation that accompanies neuronal cell loss restricts the regenerative potential of MG. Indeed, we recently found that ablation of microglia, the endogenous immune cell of the retina, dramatically improved MG-mediated retinal regeneration. This finding implicates the neuroimmune system as a key component of the regenerative response of the mammalian retina. However, little is known about the neuroimmune interface in retinal repair strategies such as endogenous regeneration. This proposal outlines studies to better understand the neuroimmune axis during MG-mediated retinal regeneration and to develop immunomodulation strategies to improve the regenerative capacity of the mammalian retina. The data generated in this proposal will be foundational to Dr. Todd's ultimate goal of becoming an independent investigator. During the K99 portion, Dr. Todd will expand his technical and theoretical expertise in neuroimmunology to accomplish his aims studying immune-glial interactions during retinal regeneration. New collaborations will be established with investigators in neuroimmunology and further training activities will prepare Dr. Todd to become a successful investigator in the field. The training portion of this proposal will take place at the University of Washington, which offers exceptional access to both research equipment and faculty expertise to assist in the accomplishment of the applicant's goals.

项目总结/文摘