AIBP-mediated neuroprotection in glaucomatous optic neuropathy

AIBP 介导的青光眼视神经病变神经保护作用

基本信息

批准号：
10659914
负责人：
SOO-HO CHOI
金额：
$ 64.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659914
关键词：
ATP-Binding Cassette Transporters Apolipoprotein A-I Autophagocytosis Axon Binding Binding Proteins Bioenergetics Biological Assay Blindness Cell Communication Cell Death Cell Survival Cells Cholesterol Cholesterol Homeostasis Clinical Research Coculture Techniques Complex Dependovirus Development Dimerization Disease Electroretinography Elements Flow Cytometry Functional disorder Genes Genus Hippocampus Glaucoma Histologic Histological Techniques Human Imaging technology In Vitro Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta LOC118430 gene Link Measures Mediating Membrane Membrane Microdomains Methods Microscopic Mitochondria Mitochondrial Proteins Mixed Function Oxygenases Molecular Molecular Analysis Muller&apos s cell Mus Nerve Degeneration Neuroglia Optic Nerve Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Pattern Physiologic Intraocular Pressure Play Primary Open Angle Glaucoma Process Protein Deficiency Protein Overexpression Protein Secretion Proteins Recombinants Recovery of Function Regulation Respiration Retina Retinal Ganglion Cells Role Signal Transduction Single Nucleotide Polymorphism Stress Synapses System TLR4 gene Technology Testing Therapeutic Therapeutic Effect Variant Vision Visual Pathways Visual System Visual evoked cortical potential Visual impairment Work complex IV cytochrome c oxidase experimental study extracellular in vivo intravitreal injection mitochondrial dysfunction neuroinflammation neuroprotection novel novel therapeutics optic nerve disorder preservation pressure prevent protein expression receptor response therapeutic evaluation tomography vector

项目摘要

Glaucoma is a leading cause of blindness worldwide and glia-driven neuroinflammation is a key element in the pathogenesis of glaucoma. Increasing evidence from clinical studies indicate that primary open-angle glaucoma is linked to single-nucleotide polymorphisms of toll-like receptor 4 (TLR4), mitochondrial cytochrome c oxidase subunit I of the oxidative phosphorylation (OXPHOS) complex-IV, ATP-binding cassette transporter A1 and Cholesterol-24S-hydroxylase, suggesting that TLR4-mediated neuroinflammation, cholesterol efflux and/or OXPHOS stress-mediated mitochondrial dysfunction play roles in glaucoma pathogenesis. ApoA-I binding protein (AIBP), encoded by the APOA1BP gene, is a secreted protein, which serves as a selective regulator of cellular cholesterol metabolism, targeting inflammatory cells via its binding to TLR4. Cholesterol depletion from inflammatory cells reduces lipid raft abundance and the membrane occupancy of receptors (such as TLR4) that mediate inflammatory signaling. Emerging evidence from our group showed that AIBP deficiency is associated with glia-driven inflammatory TLR4/interleukin-1β signaling axis and mitochondrial dysfunction in glaucomatous degeneration. In addition to protecting retinal ganglion cells (RGCs) against neuroinflammation, AIBP prevents RGC mitochondrial dysfunction in glaucomatous neurodegeneration. In preliminary studies, we demonstrated that AIBP expression is highly reduced in glaucomatous human and mouse RGCs and their axons, as well as Müller glia, and that amplification of retinal AIBP expression by adeno-associated virus delivery protects RGCs and preserves visual function in experimental glaucoma in vivo. In addition, treatment with recombinant AIBP protein promotes mitochondrial function in Müller glia against elevated pressure in vitro. Based on our previous and these findings, we propose to test the novel concept that AIBP controls retinal neuroinflammation and the RGC mitochondrial dysfunction, which lead to glaucomatous neurodegeneration, as well as to test the therapeutic potential of raising AIBP expression in the retina. The Specific Aims of this proposal are: (1) to define the mechanisms by which AIBP controls TLR4-lipid raft activation in inflammatory Müller glial cells; (2) to determine the protective mechanisms of AIBP amplification on mitochondrial network and bioenergetics in glaucomatous RGCs and Müller glial cells; and (3) to determine how therapeutic augmentation of AIBP expression impacts structural integrity and synapses linking RGCs and the central visual pathway. Our proposed studies will explore novel pathways which potentially link neuroinflammation regulation to elevated IOP-mediated mitochondrial function and cellular cholesterol metabolism. This work may also lead to the development of a new glaucoma therapy.

青光眼是全球失明的主要原因，而神经胶质驱动的神经炎症是您的关键因素青光眼的发病机理。与Toll样受体4（TLR4），线粒体细胞色素C氧化酶的单核苷酸多态性有关氧化磷酸化（OXPHOS）复合物，ATP结合盒转运蛋白A1和胆固醇-24S-羟化酶，提示TLR4介导的神经炎症，胆固醇外排和或或或或或或或或或或或或或或或od或或或或或或或或或或或或或od或或或或或或或或或或 Oxphos应激介导的米孔症功能障碍在青光眼发病机理中起着作用由apoA1bp基因编码的蛋白质（AIBP）是一种分泌的蛋白质，它可以作为选择性调节剂细胞胆固醇代谢，通过其结合TLR4靶向炎症细胞炎性细胞可减少脂质筏丰度和受体的膜占占效率（例如TLR4）介导的炎症信号传导。带有神经胶质的TLR4/白介素-1β信号轴和青光眼功能障碍退化。 RGC线粒体功能障碍在青光眼上的神经退行性研究中。青光眼的人和小鼠RGC及其轴突以及 MüllerGlia，以及通过腺相关病毒递送对视网膜AIBP Express的扩增可保护RGC 并保留体内实验性青光眼中的视觉功能。蛋白质促进Müller神经胶质中的线粒体功能，以基于我们的Prous升高。这些发现，我们建议测试AIBP控制视网膜神经炎症和您的新颖概念 RGC线粒体功能障碍，导致青光眼神经变性，以测试您在视网膜中提高AIBP表达的治疗潜力。 AIBP控制TLR4-脂筏激活炎症的机制；确定Mitchondrial网络和生物能学上AIBP扩增的保护机制青光眼RGC和Müller神经胶质细胞和（3）表达影响和突触连接RGS和我们的中央途径研究将探索新的途径，该途径可能将神经炎症调节与IOP介导的升高联系起来线粒体功能和细胞胆固醇代谢。青光眼治疗。