Context-specific angiogenic signaling in the pulmonary vasculature

肺血管系统中特定的血管生成信号传导

基本信息

批准号：
10280040
负责人：
PAUL B YU
金额：
$ 62.56万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10280040
关键词：
ACVR1 gene ACVR2B gene ACVRL1 gene Agonist Animal Model Attenuated Automobile Driving BMPR2 gene Biology Blood Circulation Blood Vessels Cell physiology Cells Clinical Coculture Techniques Complex Cultured Cells Development Disease Endothelial Cells Endothelium Family Gene Expression Genes Heart failure Hereditary hemorrhagic telangiectasia Heritability Homeostasis Human Hypertension In Vitro Investigational Therapies Ligands Lung Modeling Obstruction Outcome Pathogenesis Pathway interactions Permeability Pharmacology Phenotype Physiological Process Progressive Disease Pulmonary Circulation Pulmonary Hypertension Pulmonary Vascular Resistance Recombinants Regulation Research Role Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Smooth Muscle Myocytes Syndrome System Tachyphylaxis Therapeutic Vascular Diseases Vascular remodeling Vasodilator Agents cell growth cell motility cell type design experience functional status improved in vivo in vivo Model loss of function mutation monolayer mortality non-genetic novel novel strategies novel therapeutic intervention programs pulmonary arterial hypertension receptor recruit

项目摘要

This project describes a research program to ascertain the functions of the BMP9-BMPR2-ALK1 signaling axis in pulmonary vascular biology, and to determine its contribution to pulmonary arterial hypertension (PAH). Loss-of-function mutations in genes encoding the BMP9 signaling complex in endothelial cells—BMPR2, ALK1, co-receptor ENG, GDF2, and downstream effector SMAD9—have been implicated in heritable PAH, while the acquired deficiency of these factors and of downstream SMAD1/5/9 signaling have been hallmarks of non-genetic forms (PH). The mechanisms by which BMPR2/ALK1 signaling regulates homeostasis of the pulmonary vasculature are not known, and the manner in which dysregulated BMP9 signaling may predisposes to PAH remains incompletely understood. In support of a protective role of BMP9 signaling, treatment with recombinant BMP9 ligand attenuates PH and pulmonary vascular remodeling in several models of PH, while deficiency of circulating BMP9 is associated with portopulmonary hypertension. Paradoxically, treatment with ALK1-Fc, a BMP9 ligand trap, also ameliorates experimental PH, suggesting Janus-like, context-sensitive effects of BMP9 signaling in PAH. Aim 1 of this program includes detailed mechanistic studies to discern how distinct co-receptors and effectors recruited by BMP9 signaling may elicit disparate functions in pulmonary vascular cells. Aim 2 investigates the physiologic effects of these signals using in vitro and in vivo models of pulmonary vascular barrier function. Aim 3 examines how selective engagement of various components of the BMP9 receptor complex may impact experimental PH and pulmonary vascular remodeling. These studies leverage the extensive experience in selective modulation and targeting of the BMP/TGFb signaling pathway, and novel pharmacologic probes designed to engage various components of the signaling pathway in a highly selective and translatable fashion. This program is supported by proof-of-concept studies using human cells, and state-of-the-art models. This project builds upon the demonstrated therapeutic potential of modulating BMP/TGFb family signaling for the treatment of pulmonary vascular disease and may generate novel strategies that would overcome the limitations of current approved and investigational therapies.

该项目描述了一项研究计划，以确定 BMP9-BMPR2-ALK1 的功能肺血管生物学中的信号轴，并确定其对肺血管的贡献动脉高血压 (PAH) 编码 BMP9 信号的基因功能丧失突变。内皮细胞中的复合体——BMPR2、ALK1、共受体 ENG、GDF2 和下游效应子 SMAD9——与遗传性多环芳烃有关，而这些因素的获得性缺陷和下游 SMAD1/5/9 信号传导已成为非遗传形式 (PH) 的标志。 BMPR2/ALK1信号调节肺稳态的机制脉管系统尚不清楚，BMP9 信号传导失调的方式可能 BMP9 的保护作用尚不完全清楚。信号传导，重组 BMP9 配体治疗可减弱 PH 和肺血管多种 PH 模型中的重塑，而循环 BMP9 的缺乏与矛盾的是，ALK1-Fc（一种 BMP9 配体陷阱）也能治疗门脉性肺动脉高压。改善实验性 PH，表明 BMP9 具有类似 Janus 的、上下文相关的作用该计划的目标 1 包括详细的机制研究，以了解如何实现 PAH 中的信号传导。 BMP9 信号传导招募的不同共受体和效应器可能会在目标 2 研究这些信号在肺血管细胞中的生理效应。目标 3 检查肺血管屏障功能的体外和体内模型。 BMP9 受体复合物的各种成分的参与可能会影响实验这些研究利用了 PH 和肺血管重塑方面的丰富经验。选择性调节和靶向 BMP/TGFb 信号通路，以及新颖的药理学探针旨在参与信号通路的各个组成部分该计划得到了概念验证研究的支持。该项目基于已证明的人类细胞和最先进的模型。调节 BMP/TGFb 家族信号传导治疗肺结核的治疗潜力血管疾病，并可能产生克服血管疾病局限性的新策略目前已批准和研究的疗法。