Brain-gut-retina axis in diabetic retinopathy
糖尿病视网膜病变中的脑-肠-视网膜轴
基本信息
- 批准号:10595142
- 负责人:
- 金额:$ 55.06万
- 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
- 起止时间:2023-03-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAdaptive Immune SystemAdrenergic ReceptorAnatomyAnimalsAreaBacterial InfectionsBlood capillariesBrainCD8-Positive T-LymphocytesCell physiologyCell secretionCellsCharacteristicsCircadian RhythmsCirculationCommunicationCre lox recombination systemCytomegalovirusDataDependovirusDevelopmentDiabetes MellitusDiabetic RetinopathyDiabetic mouseDiphtheria ToxinDiseaseElectrophysiology (science)EnteralEnvironmental Risk FactorExcisionFlow CytometryFunctional disorderGeneticHealthHomeostasisHost DefenseHyperactivityHypothalamic dysfunctionHypothalamic structureIL17 geneImmuneImpairmentInflammationInflammatoryInjectionsInjuryInnate Immune SystemInsulin-Dependent Diabetes MellitusIntestinesMediatingModelingMusMycosesNerveNeuronsNeurotransmittersOctreotideOutputPathogenesisPathogenicityPathologicPhenotypePlasmaPopulationPropertyPublishingRegulatory T-LymphocyteReporterRetinaRoleSerumSignal TransductionSiteSomatostatinStreptozocinSynapsesSystemT-LymphocyteT-Lymphocyte SubsetsTestingTissuesViralcell motilitycomparison controlcytokinecytotoxicdesigner receptors exclusively activated by designer drugsdiabeticdysbiosisgain of functiongut microbiomeimmune functionimmunoregulationintestinal barrierloss of functionmicrobiotamicroorganism antigenmigrationmonocytenon-diabeticnovel strategiesoptogeneticsparaventricular nucleusperipheral bloodpharmacologicpreservationpreventprogramsrecruitresponsesingle-cell RNA sequencingsmall hairpin RNAsomatostatin analogtissue injurytooltraffickingtranscriptome sequencing
项目摘要
Summary Abstract
This application puts for the notion of a brain-gut- retinal axis that becomes dysfunctional in diabetic
retinopathy (DR). The innate immune system has been strongly implicated in the pathogenesis of DR,
but less is known about the role of the adaptive immune system. At the interface of these two systems is
a critical population of cells, Th17 cells, that typically reside in the gut during health. Th17 cells have
homeostatic properties, mediating host defense against bacterial and fungal infections; however, it
remains unclear how intestinal Th17 cells integrate diverse signals into a set of cellular programs that
allow them to maintain tissue homeostasis yet also become pathogenic, serving as primary drivers of
tissue inflammation. We have identified a critical role of somatostatinergic neurons in the paraventricular
nucleus of the hypothalamus (PVN) in regulation of immune function through “loss of function” studies
and “gain of function studies. SST expression is dramatically reduced in the PVN of diabetic animals.
Hypothalamic dysfunction, as seen in diabetes, has the capacity to induce injury directly through
hyperactivation of sympathetic nerves. Based on preliminary and published data, we put for the
hypothesis that: Diabetes-induced loss of inhibitory SST neurons in the PVN drives increased autonomic
input to the intestine shifting Th17 cells from a homeostatic to a pathologic state. Pathologic Th17 cells
leave the intestine and traffic to areas of tissue injury such as the retina in DR. In the retina the
pathologic Th17 cells secrete proinflammatory cytokines that recruitment innate immune cells into the
retina exacerbating DR. To examine this hypothesis, we propose the following aims: Aim 1: To test if
impaired function of hypothalamic SST neurons in diabetes contributes to hyperactivity of autonomic
efferents to the gut and increases activation of enteric neurons. Aim 2: To selectively ablate SST PVN
neurons (in the absence of diabetes) and evaluate if this results in increased autonomic input to the gut
and a shift from “homeostatic” Th17 cells to a “pathogenic” Th17 cells that migrate to the retina and
recruit circulating immune cells. Aim 3: To determine if maintaining hypothalamic SST levels at
nondiabetic levels in diabetic mice will preserve the function of homeostatic Th17 cells in the gut and
prevent their recruitment to the retina delaying the development of DR. Impact: SST analogues may
provide an important complementary strategy for DR management by preventing increased sympathetic
drive to the gut and Th17 cell dysfunction.
总结抽象
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHARLES J FRAZIER其他文献
CHARLES J FRAZIER的其他文献
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Endocannabinoids and tonic GABA in the dentate gyrus
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7656750 - 财政年份:2005
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Endocannabinoids and tonic GABA in the dentate gyrus
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7460588 - 财政年份:2005
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Endocannabinoids and tonic GABA in the dentate gyrus.
齿状回中的内源性大麻素和补品 GABA。
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7473458 - 财政年份:2005
- 资助金额:
$ 55.06万 - 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
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- 资助金额:
$ 55.06万 - 项目类别:
Endocannabinoids and tonic GABA in the dentate gyrus
齿状回中的内源性大麻素和补品 GABA
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6903677 - 财政年份:2005
- 资助金额:
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