Microglia-Vascular Interaction in Alteration of Blood-Retinal Barrier in Diabetic Retinopathy
小胶质细胞-血管相互作用在糖尿病视网膜病变血-视网膜屏障改变中的作用
基本信息
- 批准号:10512065
- 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:2021
- 资助国家:美国
- 起止时间:2021-10-01 至 2025-09-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAnimal ModelAstrocytesAtlasesBed OccupancyBlindnessBlood VesselsBlood-Retinal BarrierCandidate Disease GeneCell Culture TechniquesCell physiologyCell secretionCellsChemicalsChronicCommunicationComplexDataDevelopmentDiabetes MellitusDiabetic AngiopathiesDiabetic RetinopathyDiabetic mouseDiagnosisDiseaseEndothelial CellsEndotheliumEpidemicEventExtravasationFunctional disorderGene ExpressionGene Expression ProfileGene TargetingGeneral PopulationGenesGenomicsGoalsImmuneIn VitroInflammationInflammation MediatorsInflammatoryInsulin-Dependent Diabetes MellitusIntercellular JunctionsMediatorMicrogliaModelingMolecularMolecular ProfilingMuller&aposs cellNon-Insulin-Dependent Diabetes MellitusPathway interactionsPatient SelectionPatientsPericytesPermeabilityPersonsPharmaceutical PreparationsPharmacy facilityPhenotypePlayPopulationPrevalenceProcessPublic HealthRNAResearchResearch ProposalsRestRetinaRoleSeverity of illnessStructureTechnologyTestingTherapeuticTherapeutic UsesVascular Endothelial Growth FactorsVascular PermeabilitiesVeterans Health AdministrationVisionWorkaggressive therapycandidate validationcostcytokinedesigndiabeticdifferential expressiongenetic signaturehigh throughput screeninghospital bedhuman genomicsimprovedin vivoin vivo Modelinnovationintravitreal injectionmacular edemamiddle agemonocytenew therapeutic targetnext generationnovelnovel drug classnovel markernovel therapeuticsoff-patentparticipant enrollmentpreventretinal neuronsmall moleculesmall molecule librariestargeted treatmenttherapeutic targettraffickingtranscriptometranscriptomic profiling
项目摘要
Significance: Diabetes is a global epidemic with 48 million people affected in USA, and the prevalence is
expected to increase to 63 million by 2045. The disease represents a significant public health problem. Diabetes
within the Veterans Health Administration (VHA) poses a significant challenge because the estimated
prevalence of diabetes among its enrolled patients is as high as 25%, substantially higher than the general
population. Diabetes is the third most common VHA diagnosis and accounted for 25% of pharmacy costs and
over 1.7 million hospital bed days. Diabetic retinopathy, a microvascular complication of diabetes is the leading
cause of vision loss in middle-aged adults. Despite the use of therapeutics targeting the vascular endothelial
growth factor (VEGF), about two thirds of patients do not recover vision, and the effect is transient, needing
repeated intravitreal injections of drugs. Rationale: Chronic inflammation in retina plays a major role in BRB
alteration resulting in vascular leakage. Our preliminary work presents novel evidence that there is increased
influx of monocytes and activation of microglia in the retina in diabetes. The goal of this research proposal is to
determine what factors are secreted by the activated microglia and how those factors interact with vascular
cells leading to alteration of the BRB. Hypothesis: Activated microglia in the diabetic retina secrete
factors that affect pericyte-endothelial interactions leading to BRB alteration. Aims: 1)
Determine effect of microglia depletion on the retinal vasculature and structure in the context of diabetic
retinopathy, 2a) Identify and prioritize “candidate genes” by analyzing the core transcriptional signatures of
activated retinal microglia in an animal model of diabetes in relationship to blood-retinal barrier alteration.
2b) Validate the role of “microglial candidate genes” on endothelial cell permeability and blood retinal
barrier alteration in diabetes and 3) Test the druggability of the functionally validated candidate genes
using an off-patent small molecule library in cell culture models and a diabetic animal model. Design: In
this research proposal, next generation sequence (NGS) technology will be utilized to investigate the molecular
basis of alteration of the BRB in diabetes. This research will address a critical scientific gap by identifying
molecular mediators beyond VEGF that alter the BRB. Relevance: The findings may help in development of
novel biomarkers and improved therapeutic strategies targeting these molecules in both type 1 and 2 diabetes
patients that may prevent vision loss in those who poorly respond to anti-VEGF drugs. Our approach is
innovative because this proposal introduces an innovative strategy that targets the mechanisms of stabilizing
the initial step of microglia dysfunction in diabetes, a critical upstream event for the development of diabetic
macular edema.
意义:糖尿病是一种全球性流行病,在美国有4800万人受影响,
预计到2045年将增加到6300万。这种疾病是一个严重的公共卫生问题。糖尿病
在退伍军人健康管理局(VHA)内部提出了一个重大挑战,因为估计
糖尿病的患病率在其登记的患者中高达25%,大大高于一般
人口糖尿病是第三常见的VHA诊断,占药房费用的25%,
超过170万个住院日。糖尿病视网膜病变是糖尿病的主要微血管并发症,
中年人视力下降的原因。尽管使用了靶向血管内皮细胞的治疗方法,
生长因子(VEGF),约三分之二的患者不能恢复视力,并且效果是短暂的,需要
反复玻璃体内注射药物。原理:视网膜慢性炎症在BRB中起主要作用
改变导致血管渗漏。我们的初步工作提出了新的证据,
糖尿病视网膜中单核细胞的流入和小胶质细胞的激活。这项研究计划的目标是
确定激活的小胶质细胞分泌哪些因子以及这些因子如何与血管相互作用
导致BRB改变的细胞。假说:糖尿病视网膜中激活的小胶质细胞分泌
影响周细胞-内皮细胞相互作用导致BRB改变的因素。目的:
在糖尿病背景下确定小胶质细胞耗竭对视网膜血管和结构的影响
视网膜病变,2a)通过分析视网膜病变的核心转录特征来识别和优先考虑“候选基因”。
糖尿病动物模型中的活化视网膜小胶质细胞与血-视网膜屏障改变的关系。
2b)验证“小胶质细胞候选基因”对内皮细胞通透性和血视网膜色素变性的作用。
糖尿病中的屏障改变和3)测试经功能验证的候选基因的可药用性
在细胞培养模型和糖尿病动物模型中使用非专利小分子文库。设计:在
这项研究计划,下一代测序(NGS)技术将用于研究分子
糖尿病BRB改变的基础。这项研究将通过识别
VEGF以外的分子介导物改变BRB。相关性:研究结果可能有助于发展
1型和2型糖尿病中靶向这些分子的新生物标志物和改进的治疗策略
可以预防对抗VEGF药物反应不良的患者的视力丧失。我们的做法是
创新,因为这项建议引入了一种创新的战略,目标是稳定机制,
糖尿病小胶质细胞功能障碍的初始步骤,糖尿病发展的关键上游事件,
黄斑水肿
项目成果
期刊论文数量(0)
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{{ truncateString('ARUP DAS', 18)}}的其他基金
Microglia-Vascular Interaction in Alteration of Blood-Retinal Barrier in Diabetic Retinopathy
小胶质细胞-血管相互作用在糖尿病视网膜病变血-视网膜屏障改变中的作用
- 批准号:
10258513 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Novel Biomarkers and Genetics of Diabetic Retinopathy
糖尿病视网膜病变的新生物标志物和遗传学
- 批准号:
10227990 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Novel Biomarkers and Genetics of Diabetic Retinopathy
糖尿病视网膜病变的新生物标志物和遗传学
- 批准号:
10460632 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Novel Biomarkers and Genetics of Diabetic Retinopathy
糖尿病视网膜病变的新生物标志物和遗传学
- 批准号:
9982948 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Sphingosine 1-Phosphate: A New Target for Early Diabetic Retinopathy
1-磷酸鞘氨醇:早期糖尿病视网膜病变的新靶点
- 批准号:
8440051 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Sphingosine 1-Phosphate: A New Target for Early Diabetic Retinopathy
1-磷酸鞘氨醇:早期糖尿病视网膜病变的新靶点
- 批准号:
8803332 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Inflammatory Chemokines: A Novel Target in Early Diabetic Retinopathy
炎症趋化因子:早期糖尿病视网膜病变的新靶点
- 批准号:
8584290 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Inflammatory Chemokines: A Novel Target in Early Diabetic Retinopathy
炎症趋化因子:早期糖尿病视网膜病变的新靶点
- 批准号:
8441872 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Extracellular Proteinases in Ocular Neovascularization
眼部新生血管形成中的细胞外蛋白酶
- 批准号:
6893995 - 财政年份:1998
- 资助金额:
-- - 项目类别:
Extracellular Proteinases in Ocular Neovascularization
眼部新生血管形成中的细胞外蛋白酶
- 批准号:
7150288 - 财政年份:1998
- 资助金额:
-- - 项目类别:
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