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
青光眼的特征在于视网膜神经节细胞(RGC)死亡导致视力丧失。可用治疗
治疗方式继续依赖于眼内压(IOP)降低,这不足以防止进行性眼内压升高。
神经变性在相当数量的青光眼患者。在与这种致盲疾病的斗争中,
迫切需要不依赖于降低IOP的治疗策略。在本提案中,我们假设,
胰高血糖素样肽-1受体(GLP-1 R)激动剂通过以下途径防止神经退行性变
减少小胶质细胞/巨噬细胞活化和视网膜巨噬细胞浸润,进而防止反应性
星形胶质细胞增生导致RGC拯救。这一假设建立在我们先前的研究基础上,研究表明,诱导性眼内
青光眼小鼠模型中高血压触发小胶质细胞/巨噬细胞活化和反应性星形胶质细胞
在视网膜中形成。我们发现,长效GLP-1 R激动剂NLY 01治疗可抑制
小胶质细胞/巨噬细胞活化,防止反应性星形胶质细胞增生,并在IOP升高后拯救RGC。
此外,我们对保险索赔数据的检查显示,使用FDA批准的GLP-1 R激动剂治疗,
用于治疗糖尿病和减肥,与降低人类青光眼风险有关。然而,视网膜
尚未鉴定介导GLP-1 R激动剂RGC保护的细胞类型。此外,尚不清楚是否
系统性巨噬细胞浸润和/或驻留小胶质细胞转化驱动早期炎症,以及是否
NLY 01修改了此响应。最后,对NLY 01治疗的这种有利反应是否普遍存在于
诱导的IOP升高与慢性进行性青光眼遗传模型的关系尚不清楚。这项建议会
追求对评价GLP-1 R激动剂的作用机制和潜在GLP-1 R至关重要的2个特定目标
GLP-1受体激动剂可作为新型青光眼治疗药物:1)确定GLP-1受体激动剂
NLY 01在IOP升高后拯救RGC,和2)确定GLP-1 R激动剂介导的RGC的机制。
遗传性青光眼模型中的神经拯救。研究结果将确定:1)系统性细胞类型促进
NLY 01的RGC拯救,包括巨噬细胞浸润是否响应于眼部炎症而驱动早期炎症
高血压,和2)GLP-1 R激动剂NLY 01是否发挥长期抗炎作用,以挽救
DBA/2 J小鼠青光眼模型中的RGC。这项提议是一项更广泛计划的第一步,
GLP-1 R激活驱动神经元拯救的全身效应。研究结果将有助于我们进一步了解
青光眼发病机制,确定驱动NLY 01介导的RGC拯救的机制,并阐明
GLP-1 R激动剂用于青光眼治疗的潜力。
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.
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
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负责人:Qi N Cui
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依托单位:
Auditory and Visual Integration and Plasticity
-
批准号:7408193
-
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:
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: