Evaluating Mechanisms and Therapeutic Potential of (GLP-1R) Agonists for Glaucoma Treatment

评估 (GLP-1R) 激动剂治疗青光眼的机制和治疗潜力

• 批准号: 10660124
• 负责人: Qi N Cui
• 金额: $ 51.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660124
• 关键词: Address; Agonist; Antiinflammatory Effect; Astrocytes; Automobile Driving; Blindness; Body Weight decreased; Brain; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Circulation; Clinical Trials; Complement 1q; Complement 3; Cytoprotection; Data; Diabetes Mellitus; Disease; Disease Progression; Eye; FDA approved; Fluorescein-5-isothiocyanate; GLP-I receptor; Generations; Genetic; Glaucoma; Human; Immunohistochemistry; In Situ Hybridization; In Vitro; Infiltration; Inflammation; Inflammatory Response; Inherited; Interleukin-1 alpha; Knockout Mice; Knowledge; Macrophage; Macrophage Activation; Maps; Measures; Mediating; Mediator; Microglia; Microspheres; Modality; Modeling; Mus; Myeloid Cells; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Ocular Hypertension; Optic Disk; Parkinson Disease; Pathogenesis; Patients; Phenotype; Physiologic Intraocular Pressure; Process; Production; Receptor Activation; Retina; Retinal Ganglion Cells; Risk; Signal Transduction; TNF gene; Testing; Therapeutic; Translations; astrogliosis; cell type; cytokine; diabetic patient; dopaminergic neuron; experimental study; fighting; hazard; hypertensive; in vivo; insurance claims; intravitreal injection; mimetics; mouse model; neural; neuroinflammation; neuron loss; neuronal cell body; neuroprotection; novel; novel therapeutics; preservation; prevent; progressive neurodegeneration; receptor expression; response; retinal ganglion cell degeneration; symptomatic improvement; targeted treatment; tool; treatment strategy

Project Summary Glaucoma is characterized by retinal ganglion cell (RGC) death leading to vision loss. Available treatment modalities continue to rely on intraocular pressure (IOP) reduction, which is insufficient to prevent progressive neurodegeneration in a significant number of glaucoma patients. In the fight against this blinding disease, treatment strategies that do not rely on IOP-lowering are urgently needed. In this proposal, we hypothesize that glucagon-like peptide-1 receptor (GLP-1R) agonists protect against glaucomatous neurodegeneration by decreasing microglia/macrophage activation and retinal macrophage infiltration, in turn preventing reactive astrogliosis resulting in RGC rescue. This hypothesis builds upon our prior study showing that induced ocular hypertension in a mouse model of glaucoma triggers microglia/macrophage activation and reactive astrocyte formation in the retina. We found that treatment with the long-acting GLP-1R agonist NLY01 suppressed microglia/macrophage activation, prevented reactive astrogliosis, and rescued RGCs following IOP elevation. Further, our examination of insurance claims data showed that treatment with GLP-1R agonists, FDA-approved to treat diabetes and for weight loss, is associated with decreased glaucoma risk in humans. However, the retinal cell type(s) mediating GLP-1R agonists' RGC protection have not been identified. Further, it is not known whether systemic macrophage infiltration and/or resident microglia transformation drive early inflammation, and whether NLY01 modifies this response. Finally, whether this favorable response to NLY01 treatment generalizes beyond induced IOP elevation to inherited models of chronic, progressive glaucoma is unknown. This proposal will pursue 2 specific aims crucial to evaluating GLP-1R agonists' mechanism of action and the potential GLP-1R agonists hold as novel glaucoma therapy: 1) Determine the mechanisms through which the GLP-1R agonist NLY01 rescues RGCs following IOP elevation, and 2) Determine the mechanisms of GLP-1R agonist-mediated neural rescue in an inherited model of glaucoma. Findings will determine: 1) the systemic cell type(s) facilitating NLY01's RGC rescue, including whether macrophage infiltration drives early inflammation in response to ocular hypertension, and 2) whether the GLP-1R agonist NLY01 exerts a long-term anti-inflammatory effect to rescue RGCs in the DBA/2J mouse model of glaucoma. This proposal is the first step in a broader plan to disentangle systemic effects of GLP-1R activation driving neuronal rescue. Results will serve to advance our understanding of glaucoma pathogenesis, identify the mechanisms driving NLY01-mediated RGC rescue, and elucidate the potential for using GLP-1R agonists in glaucoma treatment.

项目摘要 青光眼的特征是视网膜神经节细胞（RGC）死亡导致视力丧失。可用治疗 方式继续依赖于眼内压（IOP）降低，这不足以防止渐进式 大量青光眼患者的神经变性。在与这种盲目疾病的斗争中 迫切需要不依赖于降低IOP的治疗策略。在此提案中，我们假设 胰高血糖素样肽-1受体（GLP-1R）激动剂可预防通过 减少小胶质细胞/巨噬细胞激活和视网膜巨噬细胞浸润，进而阻止反应性 星形胶质病导致RGC救援。该假设建立在我们先前的研究之上，表明诱发了眼 青光眼的小鼠模型中的高血压会触发小胶质细胞/巨噬细胞激活和反应性星形胶质细胞 视网膜中的形成。我们发现用长效GLP-1R激动剂Nly1抑制了治疗 IOP升高后，小胶质细胞/巨噬细胞激活，预防反应性星形胶质细胞增多并救出RGC。 此外，我们对保险索赔的检查数据表明，GLP-1R激动剂的治疗，FDA批准 治疗糖尿病并减轻体重，与人类青光眼风险降低有关。但是，视网膜 尚未确定介导GLP-1R激动剂的RGC保护的细胞类型。此外，还不知道是否 全身性巨噬细胞浸润和/或常驻小胶质细胞转化驱动早期炎症，以及是否是否 Nly01修改了此响应。最后，这种对NLY01处理的有利反应是否概括了 诱导的IOP升高是尚不清楚慢性，进行性青光眼的遗传模型。该提议将 追求2的特定目的对于评估GLP-1R激动剂的作用机理和潜在的GLP-1R至关重要 激动剂作为新的青光眼治疗：1）确定GLP-1R激动剂的机制 NLY01在IOP升高后营救RGC，以及2）确定GLP-1R激动剂介导的机制 神经救援在遗传的青光眼模型中。调查结果将确定：1）促进的全身细胞类型 NLY01的RGC救援，包括巨噬细胞浸润是否会驱动早期炎症。 高血压，以及2）GLP-1R激动剂NLY01是否发挥长期抗炎作用来挽救 青光眼的DBA/2J小鼠模型中的RGC。该提议是更广泛计划的第一步 GLP-1R激活驱动神经元救援的全身效应。结果将有助于提高我们的理解 青光眼发病机理，确定驱动NLY01介导的RGC救援的机制，并阐明 在青光眼治疗中使用GLP-1R激动剂的潜力。