Interrogation of the Cellular Pathogenesis of Pulmonary Hypertension

肺动脉高压的细胞发病机制的探讨

基本信息

批准号：
8197835
负责人：
Larissa A. Shimoda
金额：
$ 24.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197835
关键词：
Address Adult Affect Animals Attenuated Bone Marrow Calpain Cell Proliferation Cell physiology Cells Cessation of life Chronic Development Disease Embryo Endothelial Cells Epithelial Exposure to Fibroblasts Flow Cytometry Gene Family Gene-Modified Genetic Heart failure Hematopoietic stem cells Hereditary Disease Human Hypoxia Immunohistochemistry Knock-out Knockout Mice Label Lead Measurement Measures Medial Mediating Mesenchymal Modeling Molecular Monocrotaline Mus Mutation Myofibroblast Pathogenesis Pathway interactions Population Progressive Disease Pulmonary Hypertension Pulmonary artery structure Recruitment Activity Risk Role Screening procedure Signal Transduction Smooth Muscle Smooth Muscle Myocytes Tamoxifen Testing Therapeutic Intervention Thick Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Transplantation Vascular remodeling bone morphogenetic protein receptor type II cell type hemodynamics human TGFB1 protein inhibitor/antagonist insight member neutralizing antibody new therapeutic target novel pressure prevent promoter pulmonary arterial hypertension recombinase

项目摘要

Pulmonary arterial hypertension (PH), a progressive disease defined by an elevation in the mean pulmonary artery pressure above 25 mm Hg, leads to right heart failure and a significant risk of death. Genetic alterations in two members of the TGF beta superfamily pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-beta receptor I, ALK1, have been implicated in the pathogenesis of PH. Despite the genetic and functional significance of the TGF pathway, it is unclear how dysregulation of TGF signaling results in PAH. We hypothesize that the development of PAH results from an imbalance in TGF signaling within endothelial cells. Specifically, enhanced TGF signaling in endothelial cells promotes a phenotypic change that allows the cells to undergo endothelial-mesenchymal transition and contribute to the smooth muscle or myofibroblast cell population. This project addresses one of the fundamental questions in pulmonary hypertension, the mechanism by which altered TGF beta signaling contributes to the pathogenesis of PH. The complexity of this question is amplified by the myriad of cellular processes in which TGF beta participates and the multiple cell types (endothelial, smooth muscle, and adventitial fibroblasts) it is capable of affecting and which may influence the development of pulmonary hypertension. In order to begin addressing the molecular pathway, this project proposes to study the role of TGF beta signaling in endothelial cells. We will rely on an endothelial cell inducible deletion of TGF beta receptor II and the well-established hypoxic model of PH to demonstrate the role of endothelial cell TGF beta signaling in the development of PH. Endothelial-mesenchymal transition will be characterized by genetically tagging endothelial cells and following their fate after exposure to chronic hypoxia. Finally, we will demonstrate that TGF beta signaling is required for endothelial-mesenchymal transition and test a novel inhibitor of TGF beta mediated transition. Understanding the molecular mechanism by which this occurs can provide insight into the initiation of human PAH and the development of novel therapeutic targets.

肺动脉高压（pH）是一种进行性疾病，该疾病是由平均肺动脉压在25 mm Hg的平均动脉压的升高所定义的，可导致右心力衰竭和死亡的显着风险。 TGF Beta超家族途径的两个成员，骨形态发生蛋白受体II（BMPR II）和TGF-β受体I，ALK1的遗传改变已与pH的发病机理有关。尽管TGF途径具有遗传和功能意义，但尚不清楚TGF信号传导失调如何导致PAH。我们假设PAH的发展是由于内皮细胞中TGF信号传导失衡而导致的。具体而言，内皮细胞中增强的TGF信号传导促进了表型的变化，该变化使细胞可以进行内皮间质层次过渡，并有助于平滑肌或肌纤维细胞细胞群。该项目解决了肺动脉高压的基本问题之一，肺动脉高压是改变TGFβ信号传导有助于pH发病机理的机制。这个问题的复杂性得到了TGFβ参与的无数细胞过程以及多种细胞类型（内皮，平滑肌和外在成纤维细胞）的多种细胞过程，它能够影响并可能影响肺动脉高压的发展。为了开始解决分子途径，该项目提议研究TGFβ信号在内皮细胞中的作用。我们将依靠TGFβ受体II的内皮细胞诱导缺失和pH的良好缺氧模型来证明内皮细胞TGFβ信号在pH发展中的作用。内皮间充质转变的特征是遗传标记的内皮细胞并在暴露于慢性缺氧后的命运。最后，我们将证明内皮间充质转变需要TGFβ信号传导，并测试一种新型TGFβ介导的过渡的抑制剂。了解发生这种情况的分子机制可以提供对人PAH的起始和新型治疗靶标的发展的见解。