Characterization of the role of MIF on retinal health and disease

MIF 对视网膜健康和疾病作用的表征

• 批准号: 10673137
• 负责人: Colleen Marie Cebulla
• 金额: $ 39.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673137
• 关键词: Affect; Apoptosis; Astrocytes; Bioinformatics; Blindness; Blood flow; Blood-Retinal Barrier; Cell Death; Cells; Chick; Clinical; Complement Factor D; Confocal Microscopy; Data; Databases; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dopachrome isomerase; Epiretinal Membrane; Eye; Future; Gene Deletion; Gene Expression; Genetic; Genetic Polymorphism; Genetic Transcription; Glial Growth Factor; Gliosis; Goals; Health; IL6ST gene; Inflammation; Inflammation Mediators; Inflammatory; Ischemia; Knowledge; Libraries; LoxP-flanked allele; MIF gene; Macrophage; Mediating; Mediator; Metabolic; Microglia; Migration Inhibitory Factor; Modeling; Molecular; Muller' s cell; Mus; N-Methylaspartate; Neuroglia; Neurons; Out-Migrations; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Patient-Focused Outcomes; Photoreceptors; Play; Proteomics; Reperfusion Therapy; Research; Resolution; Retina; Retinal Detachment; Retinal Diseases; Retinopathy of Prematurity; Role; Signal Pathway; Signal Transduction; Systemic disease; Testing; Therapeutic; Up-Regulation; Vascular Diseases; Veins; Vision; antagonist; artery occlusion; clinically relevant; conditional knockout; cytokine; druggable target; excitotoxicity; genetic approach; genetic association; genome-wide; improved; inhibitor; migration; mouse model; neuron loss; neuronal survival; pharmacologic; prevent; promoter; research clinical testing; retinal damage; retinal ischemia; retinal neuron; sickle cell retinopathy; side effect; single-cell RNA sequencing; transcriptome

Abstract This research focuses on filling gaps in knowledge about the precise molecular pathways that underpin retinal inflammation and impact crosstalk from ischemic retinal diseases, including diabetic retinopathy, vascular diseases, retinopathy of prematurity, and sickle cell retinopathy. Current treatments are often inadequate to prevent vision loss, and adding selective targeting of additional inflammatory mediators may offer new vision-saving therapies. We have identified that (1) the pro- inflammatory cytokine macrophage migration inhibitor factor (MIF) is a druggable target for preventing retinal gliosis and photoreceptor loss in retinal detachment. (2) MIF is up-regulated in the N-methyl-D- aspartic acid (NMDA) damage model which simulates ischemia-mediated retinal excitotoxicity; pharmacologic and genetic inhibition of MIF increases neuronal survival in this model. (3) Clinically we identified a genetic association of MIF promoter polymorphisms with epiretinal membrane formation. Müller glia/astrocytes (MG) are the predominant components of ERM suggesting that MIF could play an important role in the pathological function of retinal glia. MIF inhibitors are in clinical evaluation for a variety of systemic diseases. While inhibition of MIF’s pro-inflammatory effects may indeed underlie the enhanced neuronal survival from MIF d-DT inhibitors, our recent findings strongly suggest that alternative mechanisms also exist. MIF is highly expressed in the Müller glia/astrocytes and it has been hypothesized to be a glial growth factor. Our preliminary data show that conditional inhibition of MIF in the MG enhances the survival of retinal neurons during damage and affects the MG JAK/STAT pathway. Herein, Specific Aim 1 will test the hypothesis that MIF inhibition promotes neuronal survival in retinal damage by activating the gp130/JAK/STAT signaling pathway of Müller glia/astrocytes. In chick and murine NMDA models, we will use pharmacologic and genetic approaches to assess the impact on MG signaling pathways and neuronal survival induced by MIF inhibition. Specific Aim 2 will test the hypothesis that conditional deletion of Müller glia/astrocyte MIF up-regulates the gp130/JAK/STAT pathway and enhances the survival of retinal neurons. In Specific Aim 3 we will develop a single cell RNA-seq database of damaged and undamaged retina treated with MIF inhibitors and/or MG-specific genetic deletion of MIF. We will comprehensively evaluate the transcriptional changes at single-cell resolution in the glia and retinal neurons that result from inhibition of MIF. This research will define the important functional relationships between MIF and signaling pathways on specific cells during retinal damage. The fundamental knowledge gained from understanding the transcriptome ‘switch’ will set the stage for future studies targeting key molecular pathways that are druggable with minimal side effects, but able to prevent and recover visual loss from retinal damage.

抽象的 这项研究重点是填补有关确切分子途径的知识的空白 缺血性视网膜疾病（包括糖尿病）的视网膜炎症和影响串扰 视网膜病变，血管疾病，早产性视网膜病变和镰状细胞视网膜病变。当前的 治疗通常是不足以防止视力丧失的，并增加了额外的选择性靶向 炎症介质可能会提供节省新的视觉疗法。我们已经确定（1） 炎性细胞因子巨噬细胞迁移抑制剂（MIF）是防止药物的靶标 残留脱离中的视网膜神经胶质病和感光受体丧失。 （2）MIF在N-甲基-D-中被上调 天冬氨酸（NMDA）损伤模型，模拟缺血介导的残留兴奋性毒性； 在该模型中，药理学和遗传抑制会增加神经元存活。 （3）我们在临床上 确定了MIF启动子多态性与前膜形成的遗传缔合。 Müller神经胶质/星形胶质细胞（MG）是ERM的主要组成部分，表明MIF可以玩 在视网膜神经胶质的病理功能中的重要作用。 MIF抑制剂正在临床评估 各种系统性疾病。虽然抑制MIF的促炎作用确实可能是基础 MIF D-DT抑制剂的神经元存活增强，我们最近的发现强烈表明 还存在替代机制。 MIF在Müller神经胶质/星形胶质细胞中高度表达，并且具有 假设我们是神经胶质生长因子。我们的初步数据表明 MG中的MIF增强了损伤期间残留神经元的存活，并影响MG JAK/STAT 路径。在此，特定目标1将检验MIF抑制促进神经元存活的假设 通过激活MüllerGlia/星形胶质细胞的GP130/JAK/Stat信号通路来进行视网膜损伤。在 小鸡和鼠NMDA模型，我们将使用药物和遗传方法来评估 对MIF抑制引起的MG信号通路和神经元存活的影响。具体目标2将 检验以下假设，即MüllerGlia/星形胶质细胞MIF的条件缺失可上调 GP130/JAK/STAT途径并增强了永久神经元的存活。在特定目标3中，我们将 开发由MIF抑制剂处理的受损和未分泌视网膜的单细胞RNA-seq数据库 和/或MG特异性遗传缺失的MIF。我们将全面评估转录 由抑制MIF导致的神经胶质和永久神经元的单细胞分辨率的变化。这 研究将定义MIF与信号通路之间的重要功能关系 在永久性损害期间的特定细胞。从理解 转录组“开关”将为未来的研究奠定阶段，以关键分子途径为目标 可吸毒，具有最小的副作用，但可以防止和恢复残留损害中的视觉损失。