Regulation of Stromal Derived Factor-1 Mediated Angiogenesis in Ischemic Brain
缺血性脑中基质衍生因子 1 介导的血管生成的调节
基本信息
- 批准号:8465924
- 负责人:
- 金额:$ 7.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:Angiogenic FactorAnimalsAntidiabetic DrugsBiological AssayBlood VesselsBlood flowBrainBrain InjuriesCXCL12 geneCXCR4 ReceptorsCXCR4 geneCaregiversCause of DeathCell DeathCellsCerebral IschemiaCerebrumCleaved cellClinicalClinical ResearchContralateralCorpus striatum structureDataDevelopmentDipeptidyl PeptidasesEndothelial CellsEnzyme-Linked Immunosorbent AssayEnzymesEventFDA approvedFibroblast Growth Factor 2Flow CytometryFoundationsGeneticGlucoseGoalsGrowthHealthHistocytochemistryIn VitroInflammatoryInjuryIschemiaIschemic StrokeKnock-outKnockout MiceLuciferasesMMP2 geneMMP9 geneMatrix MetalloproteinasesMeasuresMediatingMiddle Cerebral Artery OcclusionModelingMolecularMorbidity - disease rateMusNeural CrestNeuronsOxygenPECAM1 genePatient CarePatientsPeptide HydrolasesPlasmaPlayProcessProteinsRNARecoveryRecovery of FunctionRegulationReperfusion TherapyRodent ModelRoleSamplingSerumSideSiteStaining methodStainsStem cellsStrokeStructureTestingTherapeuticTimeTranslatingTransplantationUp-RegulationVascular Endothelial Growth FactorsVascular blood supplyWestern BlottingWorkangiogenesisartery occlusionbioluminescence imagingcell motilitycerebral arterychemokinedensitydeprivationdiabetic patientdisabilityefficacy testingimprovedin vivoinhibitor/antagonistinjuredinjury and repairmatrigelmigrationmouse modelnerve stem cellneuroblastoma cellneurogenesisneuron lossnovelpre-clinicalpreventrelating to nervous systemscaffoldscreeningsmall moleculespatiotemporalstroke recoverystroke therapy
项目摘要
DESCRIPTION (provided by applicant): Stroke is the third leading cause of morbidity and long-term disability. Due to cerebral artery occlusion, ischemic stroke causes a severe reduction in blood supply causing destruction of endothelial integrity and neuronal cell death. Indeed, patients with higher density of cerebral blood vessel show better recovery and survival after stroke. Many inflammatory chemokines support the development of vascular blood supply (angiogenesis) and progenitor cell migration to the site of injury. Particularly, the chemokine stromal derived factor (SDF1) acting via its receptor CXCR4 plays a central role in promoting angiogenesis and progenitor cell recruitment. However, SDF1 is often proteolytically cleaved and inactivated. This process may hinder neural (NPC) and endothelial progenitor cells (EPC) migration and angiogenesis necessary for brain injury repair. Thus preventing SDF1 inactivation is of clinical importance. Although the protease dipeptidyl peptidase 4 (DPPIV) is shown to cleave SDF1, its role in ischemic stroke is unknown. The goal of this proposal is to establish a ground work for evaluating the efficacy of the DPPIV inhibition in enhancing the activity of SDF1 for improved angiogenesis and brain injury repair. Our studies show a correlation between loss of DPPIV and increased levels of SDF1 resulting in increased migratory and angiogenic potential of neural crest stem cell derived neuroblastoma cells. We further observed significantly increased DPPIV expression in the post- ischemic brain. We hypothesize that following focal ischemia, DPPIV up regulation curtails SDF1 activity and thus hinders the migration of progenitor cells to the ischemic region and suppresses subsequent angiogenesis and neurogenesis. We further propose that genetic knockout or small molecule inhibitors of DPPIV increases post-ischemic SDF1 levels, which in turn enhances NPC and EPC migration and angiogenesis in ischemic brain. In this proposal, we will test the predicted inverse correlation between DPPIV expression and SDF1, and CXCR4 levels in mouse brain and serum following transient middle cerebral artery occlusion (MCAO) (Aim 1). We will examine whether genetic loss of DPPIV or small molecule inhibitor of DPPIV enhances EPC recruitment and angiogenesis in vivo ischemic brain and in an in vitro ischemic model of oxygen glucose deprivation. The luciferase expressing NPC/EPC will be transplanted into the contralateral striatum of the mice subjected to MCAO and migrating cells will be tracked using bioluminescence imaging (Aim 2). Importantly, DPPIV inhibitors are FDA approved anti-diabetic drugs that increase circulating EPCs in diabetic patients. Our studies if successful can be translated to pre-clinical and clinical studies for improved angiogenesis and neurogenesis. Results from these studies may provide strong foundation for better understanding of novel targets and mechanisms of brain injury repair and may also open up a new direction for stroke therapy.
描述(由申请人提供):中风是发病和长期残疾的第三大原因。由于脑动脉闭塞,缺血性中风导致血液供应严重减少,导致内皮完整性破坏和神经元细胞死亡。事实上,脑血管密度较高的患者在中风后表现出更好的恢复和生存。许多炎性趋化因子支持血管血液供应(血管生成)的发展和祖细胞向损伤部位的迁移。特别是,趋化因子基质衍生因子(SDF 1)通过其受体CXCR 4发挥作用,在促进血管生成和祖细胞募集中发挥核心作用。然而,SDF 1通常被蛋白水解切割和失活。这一过程可能会阻碍神经(NPC)和内皮祖细胞(EPC)的迁移和脑损伤修复所需的血管生成。因此,防止SDF 1失活具有临床重要性。虽然蛋白酶二肽基肽酶4(DPPIV)被证明可以切割SDF 1,但其在缺血性卒中中的作用尚不清楚。该提案的目标是建立一个基础工作,用于评估DPPIV抑制在增强SDF 1活性以改善血管生成和脑损伤修复方面的功效。我们的研究表明DPPIV的缺失和SDF 1水平的增加之间存在相关性,导致神经嵴干细胞衍生的神经母细胞瘤细胞的迁移和血管生成潜力增加。我们进一步观察到缺血后大脑中DPPIV表达显着增加。我们推测,局灶性缺血后,DPPIV上调减少SDF 1活性,从而阻碍祖细胞迁移到缺血区域,并抑制随后的血管生成和神经发生。我们进一步提出DPPIV的基因敲除或小分子抑制剂增加缺血后SDF 1水平,这反过来又增强了缺血脑中NPC和EPC的迁移和血管生成。在本提案中,我们将测试短暂性大脑中动脉闭塞(MCAO)后小鼠脑和血清中DPPIV表达与SDF 1和CXCR 4水平之间的预测负相关性(目的1)。我们将研究是否DPPIV或DPPIV的小分子抑制剂的遗传损失增强EPC招聘和血管生成在体内缺血性脑和体外缺血模型的氧葡萄糖剥夺。将表达荧光素酶的NPC/EPC移植到经受MCAO的小鼠的对侧纹状体中,并使用生物发光成像追踪迁移细胞(Aim 2)。重要的是,DPPIV抑制剂是FDA批准的抗糖尿病药物,可增加糖尿病患者的循环EPCs。我们的研究如果成功,可以转化为临床前和临床研究,以改善血管生成和神经发生。这些研究结果可能为更好地理解脑损伤修复的新靶点和机制提供强有力的基础,也可能为中风治疗开辟新的方向。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis.
- DOI:10.1007/s12035-016-0039-4
- 发表时间:2017-09
- 期刊:
- 影响因子:5.1
- 作者:Wesley UV;Hatcher JF;Ayvaci ER;Klemp A;Dempsey RJ
- 通讯作者:Dempsey RJ
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
UMADEVI V WESLEY其他文献
UMADEVI V WESLEY的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('UMADEVI V WESLEY', 18)}}的其他基金
Role of Dual Oxidase in post-stroke brain inflammation and injury
双氧化酶在中风后脑炎症和损伤中的作用
- 批准号:
10214199 - 财政年份:2021
- 资助金额:
$ 7.26万 - 项目类别:
Regulation of Stromal Derived Factor-1 Mediated Angiogenesis in Ischemic Brain
缺血性脑中基质衍生因子 1 介导的血管生成的调节
- 批准号:
8384158 - 财政年份:2012
- 资助金额:
$ 7.26万 - 项目类别:
P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS
P4-二肽基肽酶 IV 在外周神经发生和神经母细胞瘤中的作用
- 批准号:
8168062 - 财政年份:2010
- 资助金额:
$ 7.26万 - 项目类别:
COMPARISON OF THE PROTEOMES OF PROLIFERATING AND DIFFERENTIATING NEUROBLASTOMA C
增殖和分化神经母细胞瘤 C 的蛋白质组比较
- 批准号:
8168185 - 财政年份:2010
- 资助金额:
$ 7.26万 - 项目类别:
P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS
P4-二肽基肽酶 IV 在外周神经发生和神经母细胞瘤中的作用
- 批准号:
7959689 - 财政年份:2009
- 资助金额:
$ 7.26万 - 项目类别:
P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS
P4-二肽基肽酶 IV 在外周神经发生和神经母细胞瘤中的作用
- 批准号:
7725303 - 财政年份:2008
- 资助金额:
$ 7.26万 - 项目类别:
P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS
P4-二肽基肽酶 IV 在外周神经发生和神经母细胞瘤中的作用
- 批准号:
7609873 - 财政年份:2007
- 资助金额:
$ 7.26万 - 项目类别:
PP5-ROLE OF A TRANSMEMBRANE PROTEASE, DIPEPTIDYL PEPTIDASE IN NEUROBLASTOMAS
PP5-跨膜蛋白酶、二肽基肽酶在神经母细胞瘤中的作用
- 批准号:
7381258 - 财政年份:2006
- 资助金额:
$ 7.26万 - 项目类别:
PP5-ROLE OF A TRANSMEMBRANE PROTEASE, DIPEPTIDYL PEPTIDASE IN NEUROBLASTOMAS
PP5-跨膜蛋白酶、二肽基肽酶在神经母细胞瘤中的作用
- 批准号:
7170488 - 财政年份:2005
- 资助金额:
$ 7.26万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 7.26万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 7.26万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 7.26万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 7.26万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)