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

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:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-05 至 2028-04-30

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中文摘要
翻译
项目概要 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 治疗方式仍然依赖于降低眼压(IOP),这不足以预防进行性进展 大量青光眼患者出现神经退行性变。在对抗这种致盲疾病的过程中, 迫切需要不依赖降低眼压的治疗策略。在这个提案中,我们假设 胰高血糖素样肽-1 受体 (GLP-1R) 激动剂通过以下方式预防青光眼性神经变性: 减少小胶质细胞/巨噬细胞活化和视网膜巨噬细胞浸润,从而防止反应性 星形胶质细胞增生导致 RGC 救援。这一假设建立在我们之前的研究基础上,该研究表明诱导眼 青光眼小鼠模型中的高血压触发小胶质细胞/巨噬细胞激活和反应性星形胶质细胞 在视网膜中形成。我们发现,用长效 GLP-1R 激动剂 NLY01 治疗可抑制 小胶质细胞/巨噬细胞激活,预防反应性星形胶质细胞增生,并在眼压升高后拯救 RGC。 此外,我们对保险索赔数据的检查表明,FDA 批准的 GLP-1R 激动剂治疗 治疗糖尿病和减肥,与降低人类青光眼风险有关。然而,视网膜 介导 GLP-1R 激动剂 RGC 保护的细胞类型尚未确定。此外,尚不清楚是否 全身巨噬细胞浸润和/或常驻小胶质细胞转化驱动早期炎症,以及是否 NLY01 修改此响应。最后,这种对 NLY01 治疗的良好反应是否可以推广到其他领域? 导致慢性进行性青光眼遗传模型的眼压升高尚不清楚。该提案将 追求对评估 GLP-1R 激动剂作用机制和潜在 GLP-1R 至关重要的 2 个具体目标 激动剂作为新型青光眼疗法:1) 确定 GLP-1R 激动剂的作用机制 NLY01 在 IOP 升高后拯救 RGC,并且 2) 确定 GLP-1R 激动剂介导的机制 青光眼遗传模型中的神经救援。研究结果将确定:1) 促进的系统细胞类型 NLY01 的 RGC 拯救,包括巨噬细胞浸润是否会驱动眼部早期炎症反应 高血压,2)GLP-1R激动剂NLY01是否发挥长期抗炎作用来挽救 DBA/2J 青光眼小鼠模型中的 RGC。该提案是更广泛的计划的第一步,旨在解开 GLP-1R 激活驱动神经元救援的全身效应。结果将有助于加深我们的理解 青光眼发病机制,确定驱动 NLY01 介导的 RGC 救援的机制,并阐明 使用 GLP-1R 激动剂治疗青光眼的潜力。
英文摘要
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.
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会议论文
Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma
  • 批准号:
    10018873
  • 项目类别:
  • 资助金额:
    $22.74万
  • 财政年份:
    2019
  • 负责人:
    Qi N Cui
  • 依托单位:
Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma
  • 批准号:
    10086649
  • 项目类别:
  • 资助金额:
    $4.9万
  • 财政年份:
    2019
  • 负责人:
    Qi N Cui
  • 依托单位:
Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma
  • 批准号:
    10219262
  • 项目类别:
  • 资助金额:
    $22.74万
  • 财政年份:
    2019
  • 负责人:
    Qi N Cui
  • 依托单位:
Auditory and Visual Integration and Plasticity
  • 批准号:
    7676691
  • 项目类别:
  • 资助金额:
    $4.59万
  • 财政年份:
    2007
  • 负责人:
    Qi N Cui
  • 依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    乔安娜
  • 依托单位: