Vascular ion channels and microcirculation in neonatal urinary tract obstruction
Vascular ion channels and microcirculation in neonatal urinary tract obstruction
批准号:
9884233
负责人:
Adebowale Adebiyi
金额:
$51.24万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-01 至 2025-01-31
关键词:
AcuteAcute Renal Failure with Renal Papillary NecrosisAnabolismAnimalsAtrophicBig EndothelinBiological AssayBiological MarkersBlood VesselsBlood capillariesCalciumChildhoodChronic Kidney FailureDataDevelopmentDiagnosticDiglyceridesDiseaseEDN1 geneElectrophysiology (science)EndothelinEndothelin ReceptorEndothelin-1Endothelin-2Endothelin-3Endothelin-converting enzyme 1EventFamily suidaeFibrosisFunctional disorderGlomerular Filtration RateHistologicHomeostasisImageImpairmentInfantInflammationInjury to KidneyIntensive CareInterventionIon ChannelKidneyKidney DiseasesKidney FailureKnock-outLeadLeftLinkMediatingMicrocirculationModelingMyographyNADPH OxidaseNeonatalNewborn InfantObstructionOutcome StudyPathway interactionsPeptide HydrolasesPerfusionPerinatalPharmacologyPhysiologicalPilot ProjectsPre-Clinical ModelProcessProductionProtein IsoformsProteolytic ProcessingRat StrainsRattusReactive InhibitionReactive Oxygen SpeciesReceptor ActivationRegional Blood FlowRenal functionResearchSignal TransductionSmooth Muscle MyocytesTRPC3 ion channelTechniquesTestingTime StudyTubular formationUreteral obstructionUrineVascular DiseasesVascular Smooth MuscleVascular resistanceVasodilationWeaningcohortdiagnostic biomarkerepithelial to mesenchymal transitionextracellularhemodynamicshypoperfusionimprovedinhibitor/antagonistinnovationinterestinventionkidney vascular structuremultiphoton microscopyneonatenovelpatch clamppre-clinicalpressurepreventprotein expressionreal-time imagesreceptorreceptor operated channeltherapeutic targeturinaryurinary tract obstructionvasoconstriction
中文摘要
尿路梗阻引起肾损伤,如果不纠正,可能导致不可逆的肾功能丧失
尤其是在婴儿中。新生儿梗阻性肾病的病理生理一直是一个相当大的焦点,
几十年来,研究兴趣,但在理解方面存在重大差距,包括血管机制,
肾微循环障碍。在本申请中,我们提出了一种新颖的概念,
新生儿肾血管阻力(RVR)和急性输尿管梗阻的灌注是由反应性
氧物种驱动的肽酶内皮素转化酶1的生物合成,其蛋白水解处理
多种肾大内皮素(ET 1 -3)对其血管活性亚型的影响。ET衍生的肾二酰甘油(DAG)激活
肾血管平滑肌细胞TRPC 3通道,导致受体操作的细胞外钙进入,
血管收缩延长、RVR升高和灌注不足。为了研究这些概念,我们将利用
作为可逆性尿路梗阻的临床前模型在重症监护下维持的新生猪
在婴儿身上。这些猪和一种新的TRPC 3敲除新生大鼠品系将用于描述钙依赖性
肾血管平滑肌细胞介导1)持续低灌注,
2)肾损伤; 3)急性尿路梗阻期间和之后的肌源性肾自身调节受损。
这项申请中提出的研究将积累机制数据,不仅将提高我们的理解,
新生儿肾血管病变,但可能导致潜在的诊断标志物或治疗目标的梗阻性
新生儿肾功能不全
英文摘要
Urinary tract obstruction causes kidney injury, which, if left uncorrected, may lead to an irreversible renal loss
especially in infants. The pathophysiology of neonatal obstructive nephropathy has been a focus of considerable
research interests for decades, but significant gaps in understanding include vascular mechanisms that underlie
impairment of renal microcirculation. In the present application, we propose a novel concept that alterations of
newborn renal vascular resistance (RVR) and perfusion by acute ureteral obstruction are mediated by reactive
oxygen species-driven biosynthesis of peptidase endothelin-converting enzyme 1, which proteolytically processes
multiple renal big endothelins (ET1-3) to their vasoactive isoforms. ET-derived renal diacylglycerol (DAG) activates
renal vascular smooth muscle cell TRPC3 channels, leading to receptor-operated extracellular calcium entry,
prolonged vasoconstriction, RVR elevation, and hypoperfusion. To investigate these concepts, we will utilize
newborn pigs that are maintained under intensive care as a preclinical model for reversible urinary tract obstruction
in infants. These pigs and a novel TRPC3 knockout neonatal rat strain will be used to delineate calcium-dependent
signal transduction mechanisms in renal vascular smooth muscle cells that mediate 1) persistent hypoperfusion,
2) kidney injury, and 3) impaired myogenic renal autoregulation during and after acute urinary tract obstruction.
The proposed studies in this application will accrue mechanistic data that will not only improve our understanding
of neonatal renal vasculopathy but may lead to potential diagnostic markers or therapeutic targets for obstructive
renal insufficiency in newborns.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Urotensin II and renal insufficiency in growth-restricted infants.
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批准号:10264070
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项目类别:
-
资助金额:$55.59万
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财政年份:2020
-
负责人:Adebowale Adebiyi
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依托单位:
Control of microvascular function by ion channels
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批准号:10591881
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项目类别:
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资助金额:$5.81万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Control of microvascular function by ion channels
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批准号:10594479
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项目类别:
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资助金额:$24.44万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Control of microvascular function by ion channels
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批准号:10392350
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项目类别:
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资助金额:$46.07万
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财政年份:2020
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负责人:Adebowale Adebiyi
-
依托单位:
Vascular ion channels and microcirculation in neonatal urinary tract obstruction
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批准号:10341119
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项目类别:
-
资助金额:$56.19万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Urotensin II and renal insufficiency in growth-restricted infants.
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批准号:10469433
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项目类别:
-
资助金额:$63.64万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Vascular ion channels and microcirculation in neonatal urinary tract obstruction
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批准号:10565955
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项目类别:
-
资助金额:$53.85万
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财政年份:2020
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负责人:Adebowale Adebiyi
-
依托单位:
Control of microvascular function by ion channels
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批准号:10201230
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项目类别:
-
资助金额:$2.34万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Control of microvascular function by ion channels
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批准号:10808238
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项目类别:
-
资助金额:$1.2万
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财政年份:2020
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负责人:Adebowale Adebiyi
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依托单位:
Regulation of neonatal renal hemodynamics
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批准号:9303346
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项目类别:
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资助金额:$30.0万
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财政年份:2014
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负责人:Adebowale Adebiyi
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依托单位:
Regulation of neonatal renal hemodynamics
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批准号:9084561
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项目类别:
-
资助金额:$30.0万
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财政年份:2014
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负责人:Adebowale Adebiyi
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依托单位:
Regulation of neonatal renal hemodynamics
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批准号:9520312
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项目类别:
-
资助金额:$37.6万
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财政年份:2014
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负责人:Adebowale Adebiyi
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依托单位:
Regulation of neonatal renal hemodynamics
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批准号:8671975
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项目类别:
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资助金额:$30.0万
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财政年份:2014
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负责人:Adebowale Adebiyi
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依托单位:
Regulation of neonatal renal hemodynamics
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批准号:8879129
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项目类别:
-
资助金额:$30.0万
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财政年份:2014
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负责人:Adebowale Adebiyi
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依托单位:
Vasoregulation by IP3 receptor coupling to TRPC channels
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批准号:8049107
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项目类别:
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资助金额:$11.67万
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财政年份:2009
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负责人:Adebowale Adebiyi
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依托单位:
Vasoregulation by IP3 receptor coupling to TRPC channels
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批准号:7804568
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项目类别:
-
资助金额:$11.43万
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财政年份:2009
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负责人:Adebowale Adebiyi
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依托单位:
Vasoregulation by IP3 receptor coupling to TRPC channels
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批准号:7679753
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项目类别:
-
资助金额:$11.19万
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财政年份:2009
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负责人:Adebowale Adebiyi
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依托单位:
Vasoregulation by IP3 receptor coupling to TRPC channels
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批准号:8448105
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项目类别:
-
资助金额:$11.67万
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财政年份:2009
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负责人:Adebowale Adebiyi
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依托单位:
Vasoregulation by IP3 receptor coupling to TRPC channels
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批准号:8242006
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项目类别:
-
资助金额:$11.67万
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财政年份:2009
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负责人:Adebowale Adebiyi
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依托单位: