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

• 批准号: 10770822
• 负责人: PAUL B YU
• 金额: $ 58.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10770822
• 关键词: ACVR1 gene; ACVR2B gene; ACVRL1 gene; Animal Model; Attenuated; Automobile Driving; BMPR2 gene; Biology; Blood Vessels; Cell physiology; Cells; Circulation; Clinical; Coculture Techniques; Complex; Cultured Cells; Development; Disease; Disparate; Endothelial Cells; Endothelium; Family; Gene Expression; Genes; Genetic; Hereditary hemorrhagic telangiectasia; Heritability; Homeostasis; Human; In Vitro; Investigational Therapies; Ligands; Lung; Modeling; Obstruction; Outcome; Pathogenesis; Pathway interactions; Permeability; 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; pharmacologic; portopulmonary hypertension; programs; pulmonary arterial hypertension; pulmonary artery endothelial cell; pulmonary vascular cells; pulmonary vascular disorder; pulmonary vascular remodeling; receptor; recruit; right ventricular failure

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.

本项目描述了一项确定BMP9-BMPR2-ALK1功能的研究计划 肺血管生物学中的信号轴及其在肺循环中的作用 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和下游效应分子 Smad9-与遗传性PAH有关，而这些因子的后天缺陷 下游Smad1/5/9信号通路是非遗传型(PH)的标志。这个 BMPR2/ALK1信号调节肺内稳态的机制 血管系统是未知的，并且失调的BMP9信号可能的方式 多环芳烃的易感性仍不完全清楚。支持BMP9的保护作用 信号转导，重组BMP9配体治疗可减轻肺高压和肺血管 几种PH模型中的重构，而循环中BMP9的缺乏与 门静脉高压症。矛盾的是，用BMP9配体陷阱ALK1-Fc治疗也 改善实验性PH，提示BMP9具有Janus样的上下文敏感效应 PAH中的信号。该计划的目标1包括详细的机械研究，以辨别如何 BMP9信号通路招募的不同的辅助受体和效应器可能诱导不同的功能 肺血管细胞。目的2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。《目标3》考察了如何选择 BMP9受体复合体不同成分的结合可能会影响实验 PH与肺血管重塑。这些研究利用了以下方面的丰富经验 BMP/TGFb信号通路的选择性调制和靶向，以及新的 药理探针设计用来结合信号通路的各个组成部分 具有高度选择性和可译性的时尚。该计划得到概念验证研究的支持 使用人类细胞和最先进的模型。该项目建立在演示的基础上 BMP/TGFb家族信号转导通路在肺肿瘤治疗中的作用 血管疾病并可能产生新的策略，以克服 目前批准的和研究中的治疗方法。

项目成果

Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension.

血管生成还原：肺动脉高压微血管中 VEGF/KDR 信号传导的总体保护作用。

• DOI: 10.1161/atvbaha.123.319839
• 发表时间: 2023
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Zhong,Ying;Yu,PaulB
• 通讯作者: Yu,PaulB

Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension.

• DOI: 10.1038/s41598-022-11435-x
• 发表时间: 2022-05-12
• 期刊: Scientific reports
• 影响因子: 4.6

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

• DOI: 10.1164/rccm.202005-1761oc
• 发表时间: 2021-06-01
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Li W;Long L;Yang X;Tong Z;Southwood M;King R;Caruso P;Upton PD;Yang P;Bocobo GA;Nikolic I;Higuera A;Salmon RM;Jiang H;Lodge KM;Hoenderdos K;Baron RM;Yu PB;Condliffe AM;Summers C;Nourshargh S;Chilvers ER;Morrell NW
• 通讯作者: Morrell NW