Endothelial mechanotransduction and metabolic remodeling
Endothelial mechanotransduction and metabolic remodeling
批准号:
10468115
负责人:
JEFFREY R FINEMAN
金额:
$39.94万
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:
2020-08-20 至 2025-07-31
关键词:
AgeAnimalsApoptoticAttentionAttenuatedBioenergeticsBiomechanicsBlood PressureBlood VesselsBlood flowBlood specimenCardiopulmonaryCatabolismChildChronicCongenital Heart DefectsDataDefectDevelopmentDiseaseDisease ProgressionEndothelial CellsEndotheliumEnzymesExposure toFetal SheepGene ExpressionGene Expression ProfileGlutamineGlycolysisGrowthHeart AbnormalitiesHexokinase 2HumanHydrostatic PressureIn VitroIncidenceInterventionLaboratoriesLeadLeftLesionLigationLiquid substanceLive BirthLungMediatingMediator of activation proteinMedicalMetabolicMetabolismMitochondriaModelingMorbidity - disease rateNatural HistoryOperative Surgical ProceduresPathway interactionsPatientsPatternPentosephosphate PathwayPeriodicityPhenotypePlasmaPlayProductionPulmonary artery structureRegulationRoleSeveritiesSeverity of illnessShunt DeviceSignal PathwaySignal TransductionSourceSpecificityStimulusStretchingTestingTherapeutic InterventionValidationbasebiomarker discoverybromopyruvatec-myc Genesclinically relevantcongenital heart disorderdesignendothelial dysfunctionhemodynamicsimprovedin vivoinhibitorlamb modellipid biosynthesismechanical forcemechanotransductionmetabolomicsmortalitynitrationnoveloxidationpostnatalpreservationpressurepulmonary artery endothelial cellpulmonary vascular disorderpulmonary vascular remodelingscreeningshear stresstargeted treatmenttranscriptome sequencingvascular abnormality
中文摘要
项目摘要
肺血管疾病(PVD)是先天性心脏病患者发病率和死亡率的重要来源。
心脏病(CHD)。这些患者的PVD自然史揭示了重要的病理生理学机制,
与异常肺血流量(PBF)和压力相关的差异。心脏缺陷患者
其通过来自全身的直接压力刺激使肺脉管系统暴露于增加的流量
心室发生PVD的发生率和严重程度高于导致PBF增加的缺陷患者
一个人肺内皮细胞(EC)是疾病的不可或缺的介质,由于它们暴露于这些正常的环境中,
和异常血液动力学(机械)力,包括剪切应力、流体静压和循环应变。
我们的实验室已经开发了两种不同的、临床相关的胎羊CHD模型:(1)左肺
动脉(LPA)结扎,主要导致右肺PBF增加;(2)肺动脉分流
放置导致PBF和压力增加。我们的初步数据表明,在4-6周的
年龄、模型羔羊在内皮细胞信号传导和血管功能中表现出明显的畸变。比如说,
对来自每个羔羊模型的原代肺动脉内皮细胞(PAEC)进行RNAseq分析
显示出明显不同的基因表达模式,在离体血管中的研究显示出不同的基因表达模式。
血管反应性的改变。此外,我们已经产生了新的体内和体外数据,证明
生物力学力-流体剪切应力和压力诱导的周期性拉伸-的叠加效应导致
导致内皮功能障碍(eNOS解偶联)的细胞信号传导途径的扰动,代谢
重编程(ROS驱动的HIF-1a和c-MYC激活),以及过度增殖、抗凋亡、内皮细胞凋亡。
细胞表型基于这些数据,我们将在项目1中测试的总体假设是,
与增加的PBF和压力相比,与增加的PBF相关的机械力诱导模式化的
基因表达和血管功能的改变是PVD发生和进展的基础
与CHD有关。具体来说,我们假设单独流动通过ATP维持NO信号传导,
依赖的hsp 90活性和c-MYC介导的谷氨酰胺回补。压力诱导循环的增加
然而,牵张导致HIF-1α驱动的瓦尔堡代谢和EC过度增殖,通过增加
线粒体(mt)-ROS的产生,但以ATP依赖性hsp 90活性和NO信号传导为代价。这
总体假设将在三个相互关联但独立的具体目标中进行检验。作为当前PVD处理
方法是基于疾病的严重程度,而不是潜在的病理生物学,
拟议的研究可能导致PVD 2°至CHD的靶向治疗方法,并为其他研究提供信息。
PVD类型,其中异常机械力参与疾病进展。
英文摘要
PROJECT SUMMARY
Pulmonary vascular disease (PVD) is an important source of morbidity and mortality in patients with congenital
heart disease (CHD). The natural history of PVD in these patients reveals the important pathophysiologic
differences associated with abnormal pulmonary blood flow (PBF) and pressure. Patients with cardiac defects
that expose the pulmonary vasculature to increased flow with a direct pressure stimulus from the systemic
ventricle develop PVD with greater incidence and severity than patients with defects resulting in increased PBF
alone. Pulmonary endothelial cells (EC) are integral mediators of disease, due to their exposure to these normal
and abnormal hemodynamic (mechanical) forces including shear stress, hydrostatic pressure, and cyclic strain.
Our laboratory has developed two distinct, clinically relevant models of CHD in fetal lambs: (1) left pulmonary
artery (LPA) ligation that primarily results in increased PBF to the right lung; and (2) aortopulmonary shunt
placement that results in increased PBF and pressure. Our preliminary data demonstrate that at 4-6 weeks of
age, model lambs manifest distinct aberrations in endothelial cell signaling and vascular function. For example,
RNAseq analysis performed on primary pulmonary artery endothelial cells (PAEC) from each lamb model
demonstrates markedly distinct gene expression patterns, and studies in isolated vessels demonstrate disparate
alterations in vascular reactivity. Moreover, we have generated novel in vivo and in vitro data demonstrating that
the additive effects of the biomechanical forces—fluid shear stress and pressure induced cyclic stretch—cause
perturbations in cellular signaling pathways that result in endothelial dysfunction (eNOS uncoupling), metabolic
reprogramming (ROS driven HIF-1a, and c-MYC activation), and a hyper-proliferative, anti-apoptotic, endothelial
cell phenotype. Based on these data, the overall hypothesis we will test in Project #1, is that the distinct
mechanical forces associated with increased PBF compared to increased PBF and pressure, induce patterned
alterations in gene expression and vascular function that underlie the incidence and progression of PVD
associated with CHD. Specifically, we hypothesize that flow-alone maintains NO signaling through ATP-
dependent hsp90 activity and c-MYC-mediated glutamine anaplerosis. The addition of pressure induced cyclic
stretch, however, leads to HIF-1α driven Warburg metabolism and EC hyper-proliferation via increases in
mitochondrial (mt)-ROS production, but at the expense of ATP-dependent hsp90 activity and NO signaling. This
overall hypothesis will be tested in three inter-related, but independent, Specific Aims. As current PVD treatment
approaches are based on disease severity as opposed to underlying pathobiology, the successful completion of
the proposed studies may lead to targeted therapeutic approaches for PVD 2° to CHD, as well as inform other
types of PVD, in which abnormal mechanical forces participate in disease progression.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Animal and Clinical Core
-
批准号:10705687
-
项目类别:
-
资助金额:$66.18万
-
财政年份:2020
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Animal and Clinical Core
-
批准号:10468114
-
项目类别:
-
资助金额:$66.18万
-
财政年份:2020
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Endothelial mechanotransduction and metabolic remodeling
-
批准号:10705691
-
项目类别:
-
资助金额:$40.32万
-
财政年份:2020
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Development of an oxygen delivery biotherapeutic for the preservation of myocardial function during pediatric cardiopulmonary bypass
-
批准号:10761664
-
项目类别:
-
资助金额:$99.96万
-
财政年份:2017
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Development of an oxygen delivery biotherapeutic for the preservation of myocardial function during pediatric cardiopulmonary bypass
-
批准号:9256317
-
项目类别:
-
资助金额:$29.84万
-
财政年份:2017
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:8452072
-
项目类别:
-
资助金额:$14.13万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:7232428
-
项目类别:
-
资助金额:$13.62万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:8267026
-
项目类别:
-
资助金额:$13.51万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:9038390
-
项目类别:
-
资助金额:$15.1万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:10593956
-
项目类别:
-
资助金额:$14.29万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:7802327
-
项目类别:
-
资助金额:$12.95万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:7066690
-
项目类别:
-
资助金额:$14.27万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:7421080
-
项目类别:
-
资助金额:$11.91万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:8658121
-
项目类别:
-
资助金额:$14.41万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:10410108
-
项目类别:
-
资助金额:$18.47万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:7615701
-
项目类别:
-
资助金额:$13.16万
-
财政年份:2006
-
负责人:JEFFREY R FINEMAN
-
依托单位:
Research Training in Pediatric Critical Care Medicine
-
批准号:9920729
-
项目类别:
-
资助金额:$16.02万
-
财政年份:2005
-
负责人:JEFFREY R FINEMAN
-
依托单位:
ADMA LEVELS BEFORE AND AFTER CARDIOPULMONARY BYPASS IN CHILDREN WITH CHD
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批准号:7204903
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项目类别:
-
资助金额:$0.18万
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财政年份:2005
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负责人:JEFFREY R FINEMAN
-
依托单位:
PERINATAL PULMONARY HYPERTENSION--DEVELOPMENTAL MEDIATOR
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批准号:2902649
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项目类别:
-
资助金额:$33.61万
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财政年份:1999
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负责人:JEFFREY R FINEMAN
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依托单位:
PERINATAL PULMONARY HYPERTENSION: DEVELOPMENT MEDIATORS
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批准号:6916438
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项目类别:
-
资助金额:$45.93万
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财政年份:1999
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负责人:JEFFREY R FINEMAN
-
依托单位:
海外基金