Fibroblast Mediated Mechanisms of Pulmonary Hypertension
成纤维细胞介导的肺动脉高压机制
基本信息
- 批准号:9912845
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 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:2019-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:6-Phosphofructo-2-kinaseActivin ReceptorAddressAmplifiersAnimal ModelBMPR2 geneBlood VesselsBlood capillariesCell ProliferationCellsCessation of lifeConditioned Culture MediaDataDevelopmentDiphtheria ToxinDiseaseDisease ProgressionDrug TargetingEnergy MetabolismExtracellular MatrixFamilyFibroblastsFibrosisFructoseGlycolysisGrantHumanInheritedLeadLesionLungLung diseasesMeasuresMediatingMetabolicMetalloproteasesMitogensModelingMolecular DiseaseMusMuscleMutateMutationMyofibroblastPathogenesisPathogenicityPathway interactionsPatientsPerivascular FibrosisPhenotypePhosphorylationPopulationPulmonary HypertensionPulmonary artery structureRNA analysisResearchResearch PersonnelRespiratory physiologyRoleSignal PathwaySignal TransductionSmooth MuscleTestingTherapeuticTranslatingTreesUnited StatesUp-RegulationVascular EndotheliumVascular Smooth MuscleWorkaerobic glycolysisbaseeffective therapyexperimental studygenetic approachidiopathic pulmonary fibrosisin vivoinsightmortalitymouse modelnovel therapeuticsparacrinepreventpulmonary arterial hypertensionresponsesuicide genetranscriptome sequencing
项目摘要
PROJECT SUMMARY/ABSTRACT
Pulmonary arterial hypertension (PAH) is characterized by a severe narrowing of pre-capillary pulmonary
arteries due to a combination of increased muscularization and formation of plexiform lesions. PAH has a
high mortality rate (15% 1-year mortality) resulting in ~15,000 deaths annually in the United States alone.
Mutations in BMPR2 have been identified in >70% of patients with hereditary PAH and also some cases of
sporadic PAH; however, no new and fully effective treatments have been developed based on these findings.
In the proposed studies, we will focus on understanding the underlying molecular disease mechanisms using a
mouse model that expresses a BMPR2 mutation found in a family with hereditary PAH (BMPR2+/R899X mice).
The major focus based on exciting supporting data will be to define the potentially important but enigmatic role
of fibroblasts as disease amplifiers in BMPR2+/R899X mice. This concept is driven in large measure by
observations in patients and animal models of fibrosis localized around the vascular tree and that patients with
fibrotic lung disease (such as idiopathic pulmonary fibrosis) also have significantly heightened likelihood of
developing PAH. The fundamental question therefore is whether there is a causal relationship between
aberrant BMPR2 signaling in pulmonary fibroblasts and the development and progression of PAH. In my first
RO1 grant as an independent investigator I will test the hypothesis that BMPR2+/R899X fibroblasts become
locked into a hyper-activated and pathogenic state that is crucial for the progression to fulminant disease. To
test this hypothesis, I will identify the dysregulated signaling pathways that lead to aberrant fibroblast activation
including how a reduction in BMPR2 levels leads to aberrant activation of Activin Receptor 2A (ACVR2A).
Further, I will address how fibroblast activation in turn leads to vascular smooth muscle proliferation and
thereby contributes to PAH. In response to the previous concerns we have thoroughly revised the proposal and
provide new data showing feasibility and potential importance of the work. The intent ultimately will be that
through the insights gained we can translate these findings into new therapies by defining previously unknown
signaling pathways and anti-PAH drug targets.
项目摘要/摘要
肺动脉高压(PAH)的特征是毛细血管前肺严重狭窄。
动脉由于肌肉化增加和丛状病变的形成所致。PAH有一个
高死亡率(15%的一年死亡率)每年仅在美国就导致约15,000人死亡。
BMPR2基因突变在70%的遗传性PAH患者中被发现,也在一些病例中被发现
散发性PAH;然而,还没有基于这些发现开发出新的完全有效的治疗方法。
在拟议的研究中,我们将重点了解潜在的分子疾病的机制使用
在遗传性PAH家系(BMPR2+/R899X小鼠)中发现的表达BMPR2突变的小鼠模型。
基于激动人心的支持性数据的主要焦点将是定义潜在的重要但神秘的角色
成纤维细胞作为疾病放大因子在BMPR2+/R899X小鼠中的应用。这一概念在很大程度上是由
血管树周围纤维化的患者和动物模型的观察
纤维性肺疾病(如特发性肺纤维化)也显著增加了
发展中的多环芳烃。因此,根本的问题是,两者之间是否存在因果关系
肺成纤维细胞BMPR2信号异常与PAH的发生发展在我的第一次
RO1格兰特作为一名独立研究员,我将检验BMPR2+/R899X成纤维细胞成为
被锁定到高度激活和致病状态,这是发展为暴发性疾病的关键。至
验证这一假设,我将确定导致成纤维细胞异常激活的失调信号通路
包括BMPR2水平的降低如何导致激活素受体2A(ACVR2A)的异常激活。
此外,我将阐述成纤维细胞的激活如何反过来导致血管平滑肌的增殖和
从而对多环芳烃有贡献。为回应先前的关注,我们已彻底修订该建议,并
提供表明这项工作的可行性和潜在重要性的新数据。最终的意图将是
通过获得的洞察力,我们可以通过定义以前未知的方法将这些发现转化为新的治疗方法
信号通路和抗PAH药物靶点。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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RICHARD D MINSHALL其他文献
RICHARD D MINSHALL的其他文献
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{{ truncateString('RICHARD D MINSHALL', 18)}}的其他基金
Fibroblast Mediated Mechanisms of Pulmonary Hypertension
成纤维细胞介导的肺动脉高压机制
- 批准号:
10163897 - 财政年份:2019
- 资助金额:
$ 39.98万 - 项目类别:
Fibroblast Mediated Mechanisms of Pulmonary Hypertension
成纤维细胞介导的肺动脉高压机制
- 批准号:
10378641 - 财政年份:2019
- 资助金额:
$ 39.98万 - 项目类别:
Fibroblast Mediated Mechanisms of Pulmonary Hypertension
成纤维细胞介导的肺动脉高压机制
- 批准号:
10599245 - 财政年份:2019
- 资助金额:
$ 39.98万 - 项目类别:
Src Regulation of Lung Endothelial Barrier Function
Src 对肺内皮屏障功能的调节
- 批准号:
8059132 - 财政年份:2011
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$ 39.98万 - 项目类别:
Caveolin-1 and NO Regulate PMN-mediated Increases in Vascular Permeability
Caveolin-1 和 NO 调节 PMN 介导的血管通透性增加
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7822536 - 财政年份:2009
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Src Regulation of Lung Endothelial Barrier Function
Src 对肺内皮屏障功能的调节
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7367823 - 财政年份:2007
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Src Regulation of Lung Endothelial Barrier Function
Src 对肺内皮屏障功能的调节
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7312502 - 财政年份:2006
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