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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：
10450846
负责人：
PAUL B YU
金额：
$ 60.44万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450846
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 Hereditary hemorrhagic telangiectasia Heritability Homeostasis Human 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 Vasodilator Agents cell growth cell motility cell type design experience functional status improved in vivo in vivo Model loss of function mutation lung microvascular endothelial cells monolayer mortality non-genetic novel novel strategies novel therapeutic intervention portopulmonary hypertension programs pulmonary arterial hypertension pulmonary vascular cells pulmonary vascular disorder pulmonary vascular remodeling receptor recruit right ventricular failure

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.

这个项目描述了一个研究计划，以确定BMP9-BMPR2-ALK1的功能