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: 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
• 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

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.

本项目描述了一项研究计划，以确定BMP 9-BMPR 2-ALK 1的功能 肺血管生物学中的信号轴，并确定其对肺血管生物学的贡献。 动脉高血压（PAH）。编码BMP 9信号传导的基因中的功能缺失突变 内皮细胞中的复合物-BMPR 2、ALK 1、共受体ENG、GDF 2和下游效应物 SMAD 9-与遗传性PAH有关，而这些因子的获得性缺乏 和下游SMAD 1/5/9信号传导的改变已经成为非遗传形式（PH）的标志。的 BMPR 2/ALK 1信号调节肺内稳态的机制 血管系统是未知的，并且BMP 9信号传导失调的方式可以 PAH的易感因素仍不完全清楚。支持BMP 9的保护作用 用重组BMP 9配体治疗减轻PH和肺血管 在几种PH模型中的重塑，而循环BMP 9的缺乏与PH相关。 门脉高压特别地，用ALK 1-Fc（一种BMP 9配体捕获剂）处理也 改善实验PH，表明BMP 9的Janus样上下文敏感效应 PAH中的信号。该计划的目标1包括详细的机制研究，以了解如何 由BMP 9信号转导募集的不同的共受体和效应子可能引起不同的功能， 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考察选择性 BMP 9受体复合物的各种组分的参与可能影响实验性的 PH和肺血管重构。这些研究充分利用了 BMP/TGF β信号通路的选择性调节和靶向，以及新的 药理学探针，其被设计为在一个或多个细胞中接合信号传导途径的各种组分。 高度选择性和可翻译的时尚。该计划得到了概念验证研究的支持 使用人类细胞和最先进的模型。该项目建立在所展示的 调节BMP/TGFb家族信号传导用于治疗肺损伤的治疗潜力 血管疾病，并可能产生克服血管疾病局限性的新策略 目前已批准的和试验性治疗。