Glucose transport in the diabetic outer retina.
糖尿病外视网膜中的葡萄糖转运。
基本信息
- 批准号:9487896
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-10-01 至 2019-09-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS therapyAbateAdultAffectBackground Diabetic RetinopathyBindingBlindnessBloodBlood GlucoseBlood-Retinal BarrierCell Culture TechniquesCellsClinicalClinical TrialsDefectDevelopmentDiabetes MellitusDiabetes preventionDiabetic RetinopathyDiabetic mouseDiffusionDiseaseElectron MicroscopyElectroretinographyEventEyeFunctional disorderGenerationsGenesGlucoseGlucose TransporterGoalsHyperglycemiaHyperglycemic MiceImageIn VitroInsulinInsulin ReceptorInsulin-Dependent Diabetes MellitusLaboratoriesLeukostasisMeasuresMediatingMembraneMethodsModelingMolecularMusPathologyPatientsPhasePhotoreceptorsPlayPreventionPreventive therapyReagentReceptor SignalingRegulationResearchResourcesRetinaRetinalRetinal DiseasesRisk FactorsRoleSLC2A1 geneSerumSeveritiesSignal TransductionStructure of retinal pigment epitheliumSuperoxidesSymptomsTechniquesTestingTherapeutic InterventionTimeUnited StatesVeteransVisionWorkagedapical membranebasolateral membraneblood glucose regulationblood leaddiabetes riskdiabeticearly detection biomarkersexperimental studyglucose analogglucose monitorglucose transportglycemic controlin vivoinnovationinsulin signalingmicrovascular pathologymouse modelnovelnovel therapeuticspreventpublic health relevancesuccesstargeted treatmentubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant):
Hyperglycemia is the major risk factor for development of diabetic retinopathy. Tight control of serum glucose levels is currently viewed as the primary means to slow progression to retinopathy, but the mechanisms by which glucose enters the retina and how they become perturbed in diabetes remains unclear. Therefore, understanding the mechanism of how hyperglycemia affects the outer retina (RPE and photoreceptors) and identifying methods to ameliorate glucose-induced outer retina dysfunction and early biomarkers of diabetic retinopathy is important. Recently, it has been shown that systemic reduction of the facilitative diffusion glucose transporter, GLUT1 will reduce glucose levels in the retina; however, these studies do not provide a mechanism or means to control glucose entry specifically to the retina via the blood retinal barrier (BRB). The first objective of this proposal is to determine if reductions in GLUT1 within the RPE leads to reduced retinal glucose accumulation within the RPE/outer retina, prevention of RPE dysfunction and early biomarkers of diabetic retinopathy in mouse models of diabetes. The second objective is to investigate mechanisms of GLUT1 modulation by insulin and to determine if abrogation of insulin signal transduction in the RPE can mitigate abnormal RPE function in mouse models of diabetes by regulation of GLUT1 expression and localization. We hypothesize that (1) hyperglycemia-induced increases in the expression and redistribution of GLUT1 in the RPE mediates diabetes-associated reductions in RPE/outer retina function and early signs of retinopathy, (2) that insulin also modulates glucose transport by GLUT1 in the RPE and (3) that blockade of insulin signaling in the RPE will exacerbate retinal pathophysiology found in a mouse model of diabetes. To test these hypotheses, a mouse model of type 1 diabetes will be employed to investigate GLUT1 expression and distribution within the apical and basolateral membranes of the RPE and determine if this is concomitant with an accumulation of intracellular glucose. To determine if reductions in GLUT1 expression prevents outer retina dysfunction, a haploinsufficient Glut1+/- mouse and mice in which the Glut1 gene is specifically inactivated only within the RPE will be utilized. To additionally assess how insulin affects GLUT1-mediated glucose entry and accumulation in the retina, conditional inactivation the insulin receptor (IR) will be employed to abrogate downstream signaling from this receptor. In vitro analysis of cultured RPE cells will also be used to determine if insulin treatment alters glucose transport through regulation of GLUT1 by affecting its association with a binding partner, GIPC and/or the E3 ubiquitin ligase, Nedd4-2. These experiments will determine the role that GLUT1 plays in outer retina dysfunction as a result of hyperglycemia, elucidate how insulin is involved in GLUT1 modulation, and identify a mechanism which can be targeted for therapeutic intervention.
描述(由申请人提供):
高血糖是糖尿病视网膜病变发生的主要危险因素。目前,严格控制血糖水平被视为减缓视网膜病变进展的主要手段,但葡萄糖进入视网膜的机制以及它们如何在糖尿病中受到干扰仍不清楚。因此,了解高血糖影响外视网膜(RPE和光感受器)的机制,寻找改善葡萄糖诱导的外视网膜功能障碍的方法和糖尿病视网膜病变的早期生物标志物是非常重要的。最近,有研究表明,系统性地减少促进扩散的葡萄糖转运体GLUT1会降低视网膜中的葡萄糖水平;然而,这些研究并没有提供一种机制或手段来控制葡萄糖通过血视网膜屏障(BRB)进入视网膜。这项建议的第一个目标是确定RPE内GLUT1的减少是否导致RPE/外视网膜内的视网膜葡萄糖积累减少,预防RPE功能障碍和糖尿病小鼠糖尿病视网膜病变的早期生物标志物。第二个目的是研究胰岛素对GLUT1的调节机制,并确定取消RPE中的胰岛素信号转导是否可以通过调节GLUT1的表达和定位来减轻糖尿病小鼠RPE功能的异常。我们假设(1)高血糖诱导的GLUT1在RPE中的表达和重新分布的增加介导了糖尿病相关的RPE/外视网膜功能的降低和视网膜病变的早期迹象,(2)胰岛素还调节了GLUT1在RPE中的葡萄糖运输,(3)在RPE中阻断胰岛素信号将加剧在糖尿病小鼠模型中发现的视网膜病理生理。为了验证这些假设,将使用1型糖尿病的小鼠模型来研究GLUT1在RPE的顶膜和基侧膜中的表达和分布,并确定这是否伴随着细胞内葡萄糖的积累。为了确定GLUT1表达的减少是否可以防止视网膜外功能障碍,将利用Glut1+/-单倍体不足的小鼠和Glut1基因仅在RPE内特异性失活的小鼠。为了进一步评估胰岛素如何影响GLUT1介导的葡萄糖进入和在视网膜中的积累,条件失活的胰岛素受体(IR)将被用来取消该受体的下游信号。对培养的RPE细胞的体外分析也将被用来确定胰岛素治疗是否通过调节GLUT1与结合伙伴GIPC和/或E3泛素连接酶Nedd4-2的联系来改变葡萄糖的转运。这些实验将确定GLUT1在高血糖所致的视网膜外功能障碍中所起的作用,阐明胰岛素如何参与GLUT1的调节,并确定可作为治疗干预的靶向机制。
项目成果
期刊论文数量(0)
专著数量(0)
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Ivy S Samuels其他文献
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{{ truncateString('Ivy S Samuels', 18)}}的其他基金
Glut1 and the microvascular complications of diabetes
Glut1 与糖尿病的微血管并发症
- 批准号:
10368340 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Glut1 and the microvascular complications of diabetes
Glut1 与糖尿病的微血管并发症
- 批准号:
10539264 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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