Interventions Against the Molecular Etiology of BMPR2-induced PAH
Interventions Against the Molecular Etiology of BMPR2-induced PAH
批准号:
10352413
负责人:
JAMES D WEST
金额:
$66.29万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-01 至 2023-02-28
关键词:
3-nitrotyrosineACE2ActinsAcuteAddressAgonistAngiotensin IAngiotensin IIAngiotensin II ReceptorAnimal ModelAnimalsBMPR2 geneBlood VesselsCalcium SignalingCardiac MyocytesCardiac OutputCell CommunicationCell Culture SystemCell-Cell AdhesionCellsChronicClinicClinical TrialsCritical PathwaysCytoskeletonDefectDevelopmentDiseaseDoseElementsEndotheliumEnzymesEtiologyFamily suidaeGeneticGoalsHeartHeritabilityHourHumanHypoxiaInflammatoryInstitutional Review BoardsIntercellular JunctionsInterventionIntravenous infusion proceduresKnowledgeLinkLungMammalian CellMeasuresMediatingMediator of activation proteinMetabolicMetabolismMitochondriaModelingMolecularMusMuscle CellsMutationOralOxidative StressPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhaseProcessProgress ReportsProstaglandins IPulmonary Vascular ResistancePulse PressureRegulationRenin-Angiotensin SystemReporterRight Ventricular FunctionRight ventricular structureRightsRodentSOD2 geneSignal TransductionStressSuperoxide DismutaseSystemTestingTherapeutic EffectTimeTranslatingTranslationsVascular remodelingVasodilator Agentsanaloganimal dataarteriolebasecapillary bedcostcytokinedesignearly phase clinical trialexperimental studyheart functionheart imaginghemodynamicsimprovedimproved functioningin vivo evaluationmitochondrial dysfunctionmouse modelmutantnon-invasive imagingphase II trialpolymerizationprecursor cellpreventprimary pulmonary hypertensionpulmonary arterial hypertensionreceptorsmall moleculetraffickingvasoconstriction
中文摘要
项目摘要:
ACE 2在肺动脉高压(PAH)的治疗中显示出巨大的前景。它
纠正了许多由最常见的遗传性疾病原因引起的分子缺陷,
BMPR 2突变。它在多种PAH动物模型中逆转了疾病,包括遗传性,
缺氧和炎症模型。我们已经在人类特发性PAH患者中进行了急性测试,
显示出各种血流动力学和分子改善,包括40%的改善,
心输出量与肺血管阻力的相关降低。可惜因为
由于综合和交付方面的困难,很难将其转化为共同使用。
因此,了解其效果的关键介质是有效翻译这一信息的主要障碍。
非常有希望的干预。拟议的研究将确定关键分子
ACE 2在PAH背景下调节细胞骨架的下游作用机制
(aim 1),代谢(目标2),并改善右心室功能的心脏(目标3)。的
这些目标的统一假设是ACE 2的治疗作用主要是通过MAS 1-
介导的由抑制的BMPR 2引起的细胞骨架缺陷的校正。这些缺陷包括
细胞-细胞连接、线粒体动力学和eNOS的调节。该项目利用遗传
小鼠模型,包括一种新的远红报告小鼠,它允许对心脏进行非侵入性成像
压力,患者来源的内皮前体细胞,我们新的人工小动脉系统,
在细胞培养系统中再现脉动压力、刚度、流动和剪切,从而将人,
小鼠和新的细胞培养系统来回答这些问题。
英文摘要
Project Summary:
ACE2 shows tremendous promise in the treatment of pulmonary arterial hypertension (PAH). It
corrects many of the molecular defects caused by the most common heritable cause of disease,
BMPR2 mutation. It has reversed disease in a variety of animal models of PAH, including heritable,
hypoxic, and inflammatory models. We have tested it acutely in human idiopathic PAH patients, and
shown a variety of hemodynamic and molecular improvements, including a 40% improvement in
cardiac output with associated reduction in pulmonary vascular resistance. Unfortunately, because of
difficulties with both synthesis and delivery, it will be difficult to translate to common use.
Understanding key mediators of its effect is thus the primary barrier to effective translation of this
extraordinarily promising intervention. The proposed studies will identify the key molecular
mechanisms of downstream effect of ACE2 in the context of PAH, in regulation of the cytoskeleton
(aim 1), metabolism (aim 2), and improvements in right ventricle function in the heart (aim 3). The
unifying hypothesis to these aims is that ACE2’s therapeutic effect is primarily through MAS1-
mediated correction of cytoskeletal defects caused by suppressed BMPR2. These defects include
cell-cell junctions, mitochondrial dynamics, and regulation of eNOS. The project makes use of genetic
mouse models, including a new far-red reporter mouse which allows non-invasive imaging of heart
stress, patient-derived endothelial precursor cells, our new artificial arteriole system which accurately
reproduces pulse pressure, stiffness, flow, and shear in a cell culture system, thus combining human,
mouse, and new cell culture systems to answer these questions.
期刊论文(20)
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Precision Modeling of Pulmonary Hypertension Pathology with Induced Pluripotent Stem Cell-derived Cells.
使用诱导多能干细胞衍生细胞对肺动脉高压病理学进行精确建模。
DOI:
10.1164/rccm.201803-0480ed
发表时间:
2018
期刊:
American journal of respiratory and critical care medicine
影响因子:
24.7
作者:
[West,JamesD, Carrier,EricaJ]
通讯作者:
Carrier,EricaJ
DOI:
10.1177/2045893217729096
发表时间:
2017-10
期刊:
Pulmonary circulation
影响因子:
2.6
作者:
[Pickworth J, Rothman A, Iremonger J, Casbolt H, Hopkinson K, Hickey PM, Gladson S, Shay S, Morrell NW, Francis SE, West JD, Lawrie A]
通讯作者:
Lawrie A
DOI:
10.1164/rccm.201106-1095ed
发表时间:
2011-08
期刊:
American journal of respiratory and critical care medicine
影响因子:
24.7
作者:
[J. West]
通讯作者:
J. West
Prevalence of Schistosoma japonicum-associated Pulmonary Hypertension in China: An Echocardiography-based Assessment.
中国日本血吸虫相关肺动脉高压的患病率:基于超声心动图的评估。
DOI:
10.1513/annalsats.202012-1573rl
发表时间:
2021
期刊:
Annals of the American Thoracic Society
影响因子:
8.3
作者:
[Zeng,Xiaofang, Huang,Xiao, Rathinasabapathy,Anandharajan, Xu,Zhe, Li,Kai, Liu,Na, Chen,Huiling, Jiang,Yuandong, Zha,Lihuang, Yu,Zaixin]
通讯作者:
Yu,Zaixin
DOI:
10.4103/2045-8932.87308
发表时间:
2011-07
期刊:
Pulmonary circulation
影响因子:
2.6
作者:
[Austin ED, Menon S, Hemnes AR, Robinson LR, Talati M, Fox KL, Cogan JD, Hamid R, Hedges LK, Robbins I, Lane K, Newman JH, Loyd JE, West J]
通讯作者:
West J
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