Interaction between blood flow and ALK1 signaling in AVM development

AVM 发育中血流与 ALK1 信号传导之间的相互作用

基本信息

批准号：
9900858
负责人：
BETH L ROMAN
金额：
$ 43.47万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900858
关键词：
ACVRL1 gene Ablation Address Anemia Arteries Arteriovenous malformation BMP10 gene Biomechanics Blood Vessels Blood flow Bone Morphogenetic Proteins Brain Brain Abscess Brain hemorrhage Caliber Cardiac Output Cephalic Coagulation Process Data Development Developmental Biology Disease Distal Drainage procedure Embryo Embryonic Development Endothelial Cells Endothelium Environment Epistaxis Event Family Gastrointestinal tract structure Generations Genes Genetic Diseases Glean Goals Growth Factor Heart Heart failure Hemorrhage Hereditary hemorrhagic telangiectasia Human Image Impaired wound healing Knowledge Lasers Lead Lesion Life Ligands Light Liver Lung MADH4 gene Maintenance Mediating Medical Medicine Methods Microfluidics Modeling Molecular Morbidity - disease rate Organ Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenocopy Phenotype Play Prevalence Proteins Research Risk Role Shunt Device Signal Pathway Signal Transduction Signaling Protein Site Skin Stroke Structure of mucous membrane of nose System Testing Therapeutic Transforming Growth Factor beta Transgenic Organisms Tube Vascular Diseases Veins Visceral Work Zebrafish activin receptor-like kinase 1 angiogenesis base cell behavior cell motility design embolic stroke gastrointestinal hemodynamics macromolecule mechanical force migration mortality mutant novel planar cell polarity polarized cell postnatal prevent programs prospective receptor repaired response shear stress targeted treatment

项目摘要

PROJECT SUMMARY Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder with a prevalence of 1 in 5000 that is caused by ENG, ALK1, or SMAD4 haploinsufficiency. These genes encode proteins important in endothelial bone morphogenetic protein (BMP) signaling, which is required to prevent development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). In HHT patients, AVMs develop throughout life in skin, nasal mucosa, gastrointestinal (GI) tract, and liver and can lead to epistaxis, hemorrhage, anemia, and high-output heart failure. Congenital lesions in lung and brain may lead to brain abscess or stroke. Currently available medications for HHT patients block angiogenesis or enhance clotting. These therapeutics are not ideal: they decrease epistaxis and GI bleeds in some but not all patients and are ineffective against potentially life-threatening congenital lesions in the brain and lung. Furthermore, these agents may delay wound healing and enhance risk of severe hemorrhage and thrombotic events. Therefore, the goal of our research program is to understand HHT disease mechanism to support development of targeted medical therapies for this disease. Using a zebrafish alk1 mutant as an HHT2 model, we uncovered a two-step mechanism of AVM development. In Step 1, loss of flow-dependent Alk1 signaling enhances endothelial cell migration in the direction of flow within lumenized arteries. This aberrant migration skews endothelial cell distribution toward and enlarges caliber of more distal arterial segments. In Step 2, normally transient artery-vein connections downstream of enlarged arterial segments are retained in a flow-dependent manner, resulting in high-flow AVMs. In this work, we will explore the mechanisms that underlie these two independent flow-based signaling pathways, the first of which is abrogated with Alk1 loss, and the second of which is intact with Alk1 loss. In Aim 1, we will combine developmental biology and biomechanics approaches to determine whether flow-dependent Alk1 signaling governs arterial endothelial cell migration via control of planar cell polarity or generation of endothelial tension in live zebrafish embryos. In Aim 2, we will use zebrafish embryos and a novel microfluidic platform seeded with human endothelial cells to dissect the roles of two components of blood flow—the heart-derived circulating ALK1 ligand, BMP10, and the mechanical force of shear stress—in flow- and Alk1-dependent retrograde arterial endothelial cell migration. In Aim 3, we will test the hypothesis that AVMs represent an adaptive response to altered hemodynamic force and address the signaling mechanisms that underlie flow-dependent AVM development. These studies will shed new light on two distinct flow-dependent pathways important for HHT-associated AVM development. Mechanistic information gleaned from this work can be used to develop targeted therapeutics that 1) stop development of new AVMs by repairing flow-dependent ALK1 signaling and normalizing endothelial cell migration, or 2) slow phenotype progression by preventing flow-dependent enlargement of existing AVMs.

项目摘要遗传性出血性毛道症（HHT）是一种常染色体显性血管疾病，患病率为由ENG，ALK1或SMAD4单倍宽度引起的5000分之一。这些基因编码蛋白质很重要在内皮骨形态发生蛋白（BMP）信号中，这是防止发展的动脉与静脉之间的脆弱，直接连接，或动脉畸形（AVM）。在HHT 患者，AVM在皮肤，鼻粘膜，胃肠道（GI）和肝脏中的生命中发展引起鼻脑，出血，贫血和高输出心力衰竭。肺和大脑中的先天性病变可能会导致脑脓肿或中风。目前可用于HHT患者的药物阻止血管生成或增强凝结。这些治疗剂不是理想的：它们减少了某些但并非所有患者的脑力学和胃肠道出血并且对大脑和肺部潜在威胁生命的先天性病变无效。此外，这些药物可能会延迟伤口愈合并增加严重出血和血小板事件的风险。因此，我们的研究计划的目的是了解HHT疾病机制以支持发展针对该疾病的有针对性的医疗疗法。使用斑马鱼ALK1突变体作为HHT2模型，我们发现了 AVM开发的两步机制。在步骤1中，依赖流量的ALK1信号丢失增强内皮细胞在流体动脉内流动方向迁移。这个异常的迁移偏向内皮细胞的分布向和扩大了更圆盘动脉片段的口径。在步骤2中，通常放大动脉段下游的瞬态动脉静脉连接保留在流动依赖性中方式，导致高流量AVM。在这项工作中，我们将探讨这两个基础的机制独立的基于流动的信号通路，第一个途径与ALK1损失一起归因于此，第二个是 ALK1损失是完整的。在AIM 1中，我们将结合发育生物学和生物力学方法确定依赖流动的ALK1信号是否通过控制动脉内皮细胞迁移来控制动脉内皮细胞的迁移活斑马鱼胚胎中的平面细胞极性或内皮张力的产生。在AIM 2中，我们将使用斑马鱼胚胎和一个新型的微流体平台，并用人内皮细胞播种以剖析血流的两个组成部分 - 心脏衍生的循环ALK1配体BMP10和机械力剪切应力 - 流动和ALK1依赖性逆行动脉内皮细胞迁移。在AIM 3中，我们将测试 AVM代表对移动力改变的自适应反应的假设，并解决了基于流动依赖性AVM发育的信号传导机制。这些研究将为两个不同的流动依赖性途径对于与HHT相关的AVM开发很重要。机理从这项工作中收集的信息可用于开发针对性的治疗1）停止开发通过修复依赖流量的ALK1信号传导和标准化内皮细胞迁移的新AVM，或2）表型通过防止现有AVM的流动依赖性扩展而进展。