权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Interventions Against the Molecular Etiology of BMPR2-induced PAH

针对 BMPR2 诱导的 PAH 分子病因学的干预措施

基本信息

批准号：
10352413
负责人：
JAMES D WEST
金额：
$ 66.29万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352413
关键词：
3-nitrotyrosine ACE2 Actins Acute Address Agonist Angiotensin I Angiotensin II Angiotensin II Receptor Animal Model Animals BMPR2 gene Blood Vessels Calcium Signaling Cardiac Myocytes Cardiac Output Cell Communication Cell Culture System Cell-Cell Adhesion Cells Chronic Clinic Clinical Trials Critical Pathways Cytoskeleton Defect Development Disease Dose Elements Endothelium Enzymes Etiology Family suidae Genetic Goals Heart Heritability Hour Human Hypoxia Inflammatory Institutional Review Boards Intercellular Junctions Intervention Intravenous infusion procedures Knowledge Link Lung Mammalian Cell Measures Mediating Mediator of activation protein Metabolic Metabolism Mitochondria Modeling Molecular Mus Muscle Cells Mutation Oral Oxidative Stress Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Process Progress Reports Prostaglandins I Pulmonary Vascular Resistance Pulse Pressure Regulation Renin-Angiotensin System Reporter Right Ventricular Function Right ventricular structure Rights Rodent SOD2 gene Signal Transduction Stress Superoxide Dismutase System Testing Therapeutic Effect Time Translating Translations Vascular remodeling Vasodilator Agents analog animal data arteriole base capillary bed cost cytokine design early phase clinical trial experimental study heart function heart imaging hemodynamics improved improved functioning in vivo evaluation mitochondrial dysfunction mouse model mutant non-invasive imaging phase II trial polymerization precursor cell prevent primary pulmonary hypertension pulmonary arterial hypertension receptor small molecule trafficking vasoconstriction

项目摘要

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.

项目总结：血管紧张素转换酶2在治疗肺动脉高压(PAH)方面显示出巨大的前景。它纠正了由最常见的可遗传疾病原因造成的许多分子缺陷， BMPR2突变。它已经逆转了多种PAH动物模型的疾病，包括可遗传的，低氧和炎症模型。我们已经在人类特发性PAH患者身上进行了尖锐的测试，并且显示出各种血流动力学和分子方面的改善，包括40%的改善心输出量与肺血管阻力降低相关。不幸的是，因为由于合成和交付都有困难，很难将其转化为通用产品。因此，了解影响其效果的关键因素是有效翻译这篇文章的主要障碍非常有希望的干预措施。拟议的研究将确定关键分子多环芳烃背景下ACE2对细胞骨架调控的下游作用机制 (目标1)、新陈代谢(目标2)和改善心脏右室功能(目标3)。这个统一上述目的的假说是，ACE2的S治疗作用主要是通过MAS1-1途径实现的。 BMPR2被抑制引起的细胞骨架缺陷的介导性修复。这些缺陷包括细胞-细胞连接、线粒体动力学和eNOS的调控。该项目利用了基因小鼠模型，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应激，患者来源的内皮前体细胞，我们新的人工小动脉系统，它准确地在细胞培养系统中复制脉压、僵硬、流动和剪切，从而将人类，小鼠和新的细胞培养系统来回答这些问题。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

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

Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling.

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

Are obliterative pulmonary vascular lesions reversible?

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

Idiopathic and heritable PAH perturb common molecular pathways, correlated with increased MSX1 expression.

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