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
项目总结
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的自然病史揭示了重要的病理生理过程。
与异常肺血流(PBF)和压力相关的差异。心脏缺陷患者
使肺血管系统暴露在来自全身的直接压力刺激下的流量增加
与缺陷导致PBF增加的患者相比,脑室发生PVD的发生率和严重程度更高
独自一人。肺内皮细胞(EC)是疾病的不可或缺的媒介,因为它们暴露在这些正常的
异常血流动力学(机械)力,包括剪应力、静水压力和循环应变。
我们的实验室已经建立了两种不同的、临床相关的胎羊CHD模型:(1)左肺
动脉(LPA)结扎,主要导致右肺的PBF增加;和(2)主-肺分流
导致PBF和压力增加的放置方式。我们的初步数据显示,在4-6周内
随着年龄的增长,模型羔羊在内皮细胞信号和血管功能方面表现出明显的异常。例如,
对各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,在隔离血管中的研究显示出不同的
血管反应性的改变。此外,我们产生了新的体内和体外数据表明
生物力加性效应-流体剪应力与压力诱导的循环牵张起因
导致内皮功能障碍(eNOS解偶联)、代谢的细胞信号通路紊乱
重新编程(ROS驱动的HIF-1a和c-myc激活),以及高增殖、抗凋亡的内皮细胞
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,不同的
与增加的PBF和压力相比,与增加的PBF相关的机械力,诱导图案
PVD发生和发展的基因表达和血管功能改变
与冠心病相关。具体地说,我们假设流本身不通过ATP维持信号-
依赖HSP90活性和c-myc介导的谷氨酰胺失活。加压诱导循环
然而,拉伸导致HIF-1α驱动的Warburg代谢和EC的过度增殖,这是通过增加
线粒体(MT)-ROS的产生,但以依赖于ATP的HSP90活性和NO信号为代价。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。作为当前的PVD治疗
方法是基于疾病的严重性,而不是潜在的病理生物学,成功地完成
拟议的研究可能导致针对PVD 2°至CHD的有针对性的治疗方法,并为其他
PVD的类型,异常的机械力量参与疾病的进展。
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: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: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: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
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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
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依托单位:
海外基金