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

• 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
• 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' 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

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，并且胶质驱动的神经炎症是青光眼发病的关键因素。 青光眼的发病机制。越来越多的临床研究表明原发性开角型青光眼 与Toll样受体4（TLR 4）、线粒体细胞色素c氧化酶 氧化磷酸化（OXPHOS）复合物-IV的亚基I，ATP结合盒转运蛋白A1和 胆固醇-24S-羟化酶，表明TLR 4介导的神经炎症，胆固醇流出和/或 OXPHOS应激介导的线粒体功能障碍在青光眼发病机制中发挥作用。ApoA-I结合 APOA 1BP基因编码的AIBP蛋白是一种分泌性蛋白，它作为一种选择性调节因子， 细胞胆固醇代谢，通过与TLR 4结合靶向炎症细胞。胆固醇消耗 炎性细胞减少脂筏丰度和受体（如TLR 4）的膜占有率， 介导炎症信号传导。来自我们小组的新证据表明，AIBP缺乏与 胶质细胞驱动的炎性TLR 4/白细胞介素-1 β信号轴和线粒体功能障碍 退化除了保护视网膜神经节细胞（RGC）免受神经炎症，AIBP还可以防止 昏迷性神经变性中的RGC线粒体功能障碍在初步研究中，我们证明了 AIBP的表达在青光眼的人和小鼠RGCs及其轴突中高度降低， Müller神经胶质细胞，以及通过腺相关病毒递送的视网膜AIBP表达的扩增保护RGCs 并在体内实验性青光眼中保持视觉功能。此外，用重组AIBP治疗 蛋白质促进Müller神经胶质细胞在体外对抗高压时的线粒体功能。基于我们之前 和这些发现，我们建议测试新的概念，即AIBP控制视网膜神经炎症和视网膜神经炎性病变。 RGC线粒体功能障碍，导致神经退行性疾病，以及测试 提高视网膜中AIBP表达的治疗潜力。该提案的具体目标是：（1）定义 AIBP控制炎性Müller神经胶质细胞中TLR 4-脂筏激活的机制;（2） 确定AIBP扩增对线粒体网络和生物能量学的保护机制， 青光眼RGCs和Müller神经胶质细胞;（3）确定AIBP的治疗增强 表达影响结构完整性和连接RGC和中央视觉通路的突触。我们提出的 研究将探索新的途径，这些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。这项工作也可能导致开发一种新的 青光眼治疗