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 这项研究的重点是填补有关精确分子途径的知识空白 加剧视网膜炎症并影响缺血性视网膜疾病（包括糖尿病）的串扰 视网膜病变、血管疾病、早产儿视网膜病变和镰状细胞性视网膜病变。当前的 治疗通常不足以预防视力丧失，并且需要选择性地针对其他 炎症介质可能提供新的视力挽救疗法。我们已经确定（1）亲 炎症细胞因子巨噬细胞迁移抑制因子（MIF）是预防疾病的药物靶标 视网膜神经胶质增生和视网膜脱离中的光感受器丧失。 (2) MIF在N-甲基-D-上调 天冬氨酸（NMDA）损伤模型，模拟缺血介导的视网膜兴奋性毒性； MIF 的药理学和遗传抑制可增加该模型中神经元的存活率。 (3)临床上我们 确定了 MIF 启动子多态性与视网膜前膜形成的遗传关联。 Müller 胶质细胞/星形胶质细胞 (MG) 是 ERM 的主要成分，表明 MIF 可以发挥作用 在视网膜神经胶质细胞的病理功能中起重要作用。 MIF 抑制剂正在进行临床评估 各种全身性疾病。虽然抑制 MIF 的促炎作用确实可能是 MIF d-DT 抑制剂可增强神经元存活率，我们最近的研究结果强烈表明 还存在替代机制。 MIF 在 Müller 胶质细胞/星形胶质细胞中高度表达，并且具有 被推测为神经胶质生长因子。我们的初步数据表明，条件抑制 MG 中的 MIF 增强损伤期间视网膜神经元的存活并影响 MG JAK/STAT 途径。在此，具体目标 1 将检验 MIF 抑制促进神经元存活的假设 通过激活 Müller 胶质细胞/星形胶质细胞的 gp130/JAK/STAT 信号通路来减轻视网膜损伤。在 鸡和小鼠 NMDA 模型，我们将使用药理学和遗传学方法来评估 MIF 抑制对 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：条件性删除 Müller 胶质细胞/星形胶质细胞 MIF 上调 gp130/JAK/STAT 通路并增强视网膜神经元的存活。在具体目标 3 中，我们将 开发经 MIF 抑制剂处理的受损和未受损视网膜的单细胞 RNA-seq 数据库 和/或 MG 特异性 MIF 基因缺失。我们将全面评估转录 抑制 MIF 导致神经胶质细胞和视网膜神经元的单细胞分辨率发生变化。这 研究将确定 MIF 和信号通路之间的重要功能关系 视网膜损伤期间的特定细胞。通过理解所获得的基础知识 转录组“开关”将为未来针对关键分子途径的研究奠定基础 可药物治疗，副作用最小，但能够预防和恢复视网膜损伤引起的视力丧失。