Evaluating Mechanisms and Therapeutic Potential of (GLP-1R) Agonists for Glaucoma Treatment
Evaluating Mechanisms and Therapeutic Potential of (GLP-1R) Agonists for Glaucoma Treatment
批准号:
10660124
负责人:
Qi N Cui
金额:
$51.33万
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
关键词:
AddressAgonistAntiinflammatory EffectAstrocytesAutomobile DrivingBlindnessBody Weight decreasedBrainCell DeathCell SurvivalCell physiologyCellsChronicCirculationClinical TrialsComplement 1qComplement 3CytoprotectionDataDiabetes MellitusDiseaseDisease ProgressionEyeFDA approvedFluorescein-5-isothiocyanateGLP-I receptorGenerationsGeneticGlaucomaHumanImmunohistochemistryIn Situ HybridizationIn VitroInfiltrationInflammationInflammatory ResponseInheritedInterleukin-1 alphaKnockout MiceKnowledgeMacrophageMacrophage ActivationMapsMeasuresMediatingMediatorMicrogliaMicrospheresModalityModelingMusMyeloid CellsNatureNerve DegenerationNeurodegenerative DisordersNeuronsNewly DiagnosedNon-Insulin-Dependent Diabetes MellitusOcular HypertensionOptic DiskParkinson DiseasePathogenesisPatientsPhenotypePhysiologic Intraocular PressureProcessProductionReceptor ActivationRetinaRetinal Ganglion CellsRiskSignal TransductionTNF geneTestingTherapeuticTranslationsastrogliosiscell typecytokinediabetic patientdopaminergic neuronexperimental studyfightinghazardhypertensivein vivoinsurance claimsintravitreal injectionmimeticsmouse modelneuralneuroinflammationneuron lossneuronal cell bodyneuroprotectionnovelnovel therapeuticspreservationpreventprogressive neurodegenerationreceptor expressionresponseretinal ganglion cell degenerationsymptomatic improvementtargeted treatmenttooltreatment strategy
中文摘要
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。可用的治疗方法
治疗方式继续依赖于降低眼压,这不足以防止渐进性
相当数量的青光眼患者出现神经变性。在与这种致盲疾病的斗争中,
迫切需要不依赖于降低眼压的治疗策略。在这项提案中,我们假设
胰升糖素样肽-1受体(GLP-1R)激动剂通过以下途径预防青光眼神经变性
减少小胶质细胞/巨噬细胞的激活和视网膜巨噬细胞的渗透,进而阻止反应性
星形胶质细胞增生症导致RGC抢救。这一假说建立在我们之前的研究基础上,该研究表明诱导眼
小鼠青光眼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
在视网膜上形成。我们发现,长效GLP-1R激动剂NLY01的治疗抑制了
激活小胶质细胞/巨噬细胞,防止反应性星形胶质细胞增生,并在眼压升高后挽救视网膜节细胞。
此外,我们对保险索赔数据的检查显示,FDA批准的GLP-1R激动剂治疗
治疗糖尿病和减肥,与降低人类患青光眼的风险有关。然而,视网膜
介导GLP-1R激动剂RGC保护作用的细胞类型(S)尚未确定。此外,目前还不知道
全身性巨噬细胞浸润和/或常驻小胶质细胞转化推动早期炎症,以及
NLY01修改此响应。最后,这种对NLY01治疗的有利反应是否超出了
遗传性慢性进行性青光眼模型引起的眼压升高尚不清楚。这项提议将
追求两个对评估GLP-1R激动剂的作用机制和潜在的GLP-1R至关重要的特定目标
作为青光眼新疗法的激动剂:1)确定GLP-1R激动剂的机制
NLY01对高眼压后视网膜神经节细胞的保护作用;2)确定GLP-1R激动剂介导的机制
遗传性青光眼模型的神经挽救。研究结果将确定:1)系统细胞类型(S)促进
《NLY01》S RGC救援,包括巨噬细胞浸润是否推动眼部早期炎症反应
高血压,以及2)GLP-1R激动剂NLY01是否具有长期抗炎作用
视网膜神经节细胞在DBA/2J小鼠青光眼模型中的作用这项提议是一个更广泛的解决方案的第一步。
GLP-1R激活驱动神经营救的系统效应。结果将有助于增进我们的理解
青光眼的发病机制,确定NLY01介导的RGC挽救的机制,并阐明
在青光眼治疗中使用GLP-1R激动剂的可能性。
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma
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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
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批准号:10086649
-
项目类别:
-
资助金额:$4.9万
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财政年份:2019
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负责人:Qi N Cui
-
依托单位:
Mitochondrial Respiratory Chain Dysfunction in Primary Open Angle Glaucoma
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批准号:10219262
-
项目类别:
-
资助金额:$22.74万
-
财政年份:2019
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负责人:Qi N Cui
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依托单位:
Auditory and Visual Integration and Plasticity
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批准号:7676691
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项目类别:
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资助金额:$4.59万
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财政年份:2007
-
负责人:Qi N Cui
-
依托单位:
Auditory and Visual Integration and Plasticity
-
批准号:7408193
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项目类别:
-
资助金额:$4.57万
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财政年份:2007
-
负责人:Qi N Cui
-
依托单位:
Auditory and Visual Integration and Plasticity
-
批准号:7488897
-
项目类别:
-
资助金额:$4.57万
-
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
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: