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.

该项目描述了一个研究计划，以确定BMP9-BMPR2-Alk1的功能肺血管生物学中的信号轴，并确定其对肺部的贡献动脉高血压（PAH）。编码BMP9信号传导的基因功能丧失突变内皮细胞中的复合物-BMPR2，ALK1，共受体ENG，GDF2和下游效应器 smad9-在可遗传的pah中暗示了这些因素的不足下游SMAD1/5/9信号传导是非遗传形式（pH）的标志。这 BMPR2/ALK1信号传导调节肺稳态的机制脉管系统尚不清楚，BMP9信号失调的方式可能 PAH的易感性仍然不完全理解。支持BMP9的受保护作用信号传导，重组BMP9配体的治疗会减弱pH和肺血管在几种pH模型中进行重塑，而循环BMP9的缺乏却与波经肺高血压。矛盾的是，用ALK1-FC治疗BMP9配体陷阱，改善实验pH，表明BMP9类似Janus的上下文敏感效应在PAH中发出信号。该计划的目标1包括详细的机械研究，以辨别如何 BMP9信号募集的不同的共受体和效果可能会引起不同的功能肺血管细胞。 AIM 2使用IN研究这些信号的生理效应肺血管屏障功能的体外和体内模型。 AIM 3检查了选择性 BMP9受体复合物的各个组件的参与可能会影响实验 pH和肺血管重塑。这些研究利用了丰富的经验 BMP/TGFB信号通路的选择性调制和靶向靶向旨在参与信号通路的各种组件的药理问题高度选择性和可翻译的时尚。该计划得到概念证明研究的支持使用人类细胞和最先进的模型。这个项目建立在已显示的调节BMP/TGFB家族信号的治疗潜力以治疗肺部血管疾病，可能会产生新的策略，以克服当前批准和研究疗法。