Bone Marrow Neuropathy Drives Diabetic Retinopathy
Bone Marrow Neuropathy Drives Diabetic Retinopathy
批准号:
8731390
负责人:
Steven F Abcouwer
金额:
$51.76万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-09-07 至 2016-08-31
关键词:
AddressAdhesionsAdoptive TransferAdultAgeBehaviorBiological ModelsBlindnessBlood CirculationBlood VesselsBlood capillariesBone MarrowBone Marrow CellsCCL2 geneCX3CL1 geneCalcitonin Gene-Related PeptideCapillary PermeabilityCell CountCell Culture TechniquesCellsChemicalsChemotactic FactorsChimera organismCircadian RhythmsCoupledDenervationDevelopmentDiabetes MellitusDiabetic AngiopathiesDiabetic RetinopathyDiabetic mouseDropoutEndothelial CellsEndotheliumEnzyme-Linked Immunosorbent AssayEquilibriumErythrocytesExhibitsFCGR3B geneFlow CytometryFractalkineFunctional disorderFundingGenerationsGlucoseHematopoiesisHematopoietic stem cellsHumanImmunohistochemistryIn VitroIndividualInflammationInflammatoryInflammatory ResponseLeadLeukostasisLigandsLinkLocationMacrophage Colony-Stimulating FactorMicrogliaModelingMusNeurogliaNeuronsNeuropathyNeuropeptidesNeurotransmittersNorepinephrineOperative Surgical ProceduresOutcomePathogenesisPathologyPermeabilityPhasePhysiologyPopulationPreventionProductionPropertyProteinsRecruitment ActivityRegulationRetinaRetinalRoleSignal TransductionSimulateSourceStem cellsStromal CellsSubstance PSurface AntigensTestingTherapeuticTimeWild Type MouseWorkbasebonecapillarychemokinecytokinediabeticimmunoreactivityin vivomacrogliamonocytenerve supplynoradrenergicnovelpreventprogenitorreceptorrelating to nervous systemrepairedrestorationretina circulationtype I diabetic
中文摘要
描述(申请人提供):在之前的资助期间,我们证明了糖尿病患者和小鼠表现出内皮祖细胞功能障碍。由于糖尿病引起的骨髓神经病变,这些骨髓来源的细胞以一种异常的方式释放到循环中。这种BM神经病导致这些细胞进入循环的昼夜释放的失调。这些BM变化先于糖尿病视网膜病变(DR)的发展,首次将糖尿病BM神经病变与DR联系起来。糖尿病小鼠的BM上清液含有高水平的单核/巨噬细胞集落刺激因子(M-CSF),糖尿病小鼠视网膜和循环中的单核细胞数量增加。基于这些发现,我们假设:糖尿病BM失神经导致HSC/祖细胞功能障碍,导致产生的单核细胞总数增加,再加上视网膜胶质细胞CCL2(单核细胞化学吸引蛋白-1)的表达增加,导致糖尿病视网膜中促炎(M1)单核细胞水平过高。此外,功能障碍的神经元表达CX3CL1(Fractalkine)的水平降低会增强驻留的小胶质细胞的炎症反应。这种失衡导致神经炎症,加速了DR的发病。我们将通过在体外和体内同时探索以下目标来验证这一假说:目的1:确定糖尿病引起的骨髓神经病变是否与骨髓基质细胞产生M-CSF增加有关,后者将造血转移到过多单核细胞的产生,特别是促炎的Gr1/CCR2/CX3CR1lo单核细胞,而不是保护性的Gr1-/CCR2-/CX3CR1单核细胞。目的:探讨CCL2和CX3CL1在糖尿病视网膜病变(DR)炎症反应中的作用,以及恢复单核细胞CCR2 CX3CR1lo和CCR2-/CX3CR1的平衡,同时恢复视网膜血管内皮祖细胞水平是否能阻止T1D小鼠DR逆转。目的3:我们的假设预测,循环中的促炎细胞Gr1/CCR2 I/CX3CR1lo将导致内皮细胞激活,促进白细胞停滞,导致视网膜通透性增强,而Gr1-/CCR2-/CX3CR1hi细胞将保护糖尿病时的BRB。我们将研究操纵这些亚群对DR进展的影响,以单核细胞亚型为靶点可能是预防和治疗DR的理想策略。CellMax?
英文摘要
DESCRIPTION (provided by applicant): In the previous funding period, we demonstrated that diabetic individuals and mice demonstrate dysfunctional endothelial progenitor cells. These bone marrow (BM) derived cells are released into the circulation in an abnormal manner due to diabetes-induced BM neuropathy. This BM neuropathy leads to dysregulation in the circadian release of these cells into the circulation. These BM changes precede development of diabetic retinopathy (DR) linking BM neuropathy for the first time to DR. Diabetic BM supernatants, but not control, contain high levels of monocyte/macrophage-colony stimulating factor (M-CSF) and diabetic mice exhibit an increase number of monocytes in the retina and circulation. Based on these findings, we hypothesize that: Diabetic BM denervation initiates HSC/progenitor dysfunction that leads to an increase in total monocytes generated, this, coupled with increased expression of CCL2 (monocyte chemoattractent protein-1) by retinal glia results in excessive levels of the pro-inflammatory (M1) monocytes in the diabetic retina. In addition, diminished levels of CX3CL1 (fractalkine) expression by dysfunctional neurons heightens the inflammatory response of resident microglia. This imbalance leads to a neural inflammation that accelerates DR pathogenesis. We will test this hypothesis both in vitro and in vivo through the simultaneous exploration of the following aims: Aim 1: To determine whether diabetes induced BM neuropathy is responsible for increased M-CSF production by BM stromal cells which shifts hematopoiesis towards generation of excessive numbers of monocytes, in particular pro-inflammatory Gr1+/CCR2+/CX3CR1lo monocytes, rather than the protective Gr1-/CCR2-/CX3CR1hi monocytes. Aim 2: To determine the roles of CCL2 and CX3CL1 in DR inflammation and to test whether restoration of the balance of CCR2+CX3CR1lo and CCR2-/CX3CR1hi monocytes and simultaneous restoration of levels of endothelial progenitors to retinal vasculature will prevent o reverse DR in T1D mice. Aim 3: Our hypothesis predicts that circulating pro- inflammatory Gr1+/CCR2+i/CX3CR1lo cells will cause endothelial cell activation, promote leukostasis and result in enhanced retinal permeability whereas Gr1-/CCR2-/CX3CR1hi cells will protect the BRB in diabetes. We will examine the effects of manipulating these subsets on the progression of DR. Targeting monocyte subtypes may represent an ideal strategy for DR prevention and treatment. CellMax?
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