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.

项目概要遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传性血管疾病，其患病率五千分之一的人是由 ENG、ALK1 或 SMAD4 单倍体不足引起的，这些基因编码重要的蛋白质。内皮骨形态发生蛋白 (BMP) 信号传导，这是防止动脉和静脉之间脆弱的直接连接，或 HHT 中的动静脉畸形 (AVM)。在患者的一生中，AVM 会在皮肤、鼻粘膜、胃肠道 (GI) 和肝脏中发展，并可能导致鼻衄、出血、贫血和高输出量心力衰竭可能导致肺和脑的先天性病变。目前可用于 HHT 患者的药物可阻止或增强血管生成。这些疗法并不理想：它们减少了一些但不是所有患者的鼻出血和胃肠道出血。对大脑和肺部可能危及生命的先天性病变无效。这些药物可能会延迟伤口愈合并增加严重出血和血栓事件的风险。因此，我们研究计划的目标是了解 HHT 疾病机制以支持发展我们发现，使用斑马鱼 alk1 突变体作为 HHT2 模型来治疗这种疾病。 AVM 发展的两步机制在步骤 1 中，流依赖性 Alk1 信号传导的丧失增强。内皮细胞在腔化动脉内沿血流方向迁移。通常在步骤 2 中，内皮细胞向更远端动脉段分布并扩大其口径。扩大动脉段下游的短暂动静脉连接保留在血流依赖性中在这项工作中，我们将探索这两种方式背后的机制。独立的基于流的信号通路，其中第一个信号通路因 Alk1 丢失而被废除，第二个信号通路在目标 1 中，我们将结合发育生物学和生物力学方法。确定流依赖性 Alk1 信号传导是否通过控制来控制动脉内皮细胞迁移在目标 2 中，我们将使用活体斑马鱼胚胎中的平面细胞极性或内皮张力的产生。斑马鱼胚胎和接种人内皮细胞的新型微流体平台来剖析血流的两个组成部分——心脏来源的循环 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。在目标 3 中，我们将测试。假设 AVM 代表对改变的血流动力学的适应性反应并解决这些研究将为血流依赖性 AVM 发育提供新的线索。两种不同的血流依赖性途径对于 HHT 相关的 AVM 发展很重要。从这项工作中收集的信息可用于开发靶向疗法，1）阻止开发通过修复血流依赖性 ALK1 信号传导并使内皮细胞迁移正常化来产生新的 AVM，或 2) 缓慢通过防止现有 AVM 的血流依赖性扩大来抑制表型进展。