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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细血管扩张症（HHT）是一种常染色体显性遗传的血管疾病， 1/5000由ENG、ALK 1或SMAD 4单倍不足引起。这些基因编码重要的蛋白质在内皮骨形态发生蛋白（BMP）信号，这是必要的，以防止发展，动脉和静脉之间脆弱的直接连接，或动静脉畸形（AVM）。在HHT 在患者中，AVM在皮肤、鼻粘膜、胃肠道（GI）和肝脏中终生发生，并可导致鼻衄出血贫血和高输出量心力衰竭肺和脑的先天性病变可能导致脑脓肿或中风目前可用于HHT患者的药物阻断血管生成或增强血管生成。凝血这些疗法并不理想：它们在某些但不是所有患者中减少鼻出血和胃肠道出血并且对脑和肺中可能危及生命的先天性病变无效。此外，委员会认为，这些药剂可能延迟伤口愈合并增加严重出血和血栓形成事件的风险。因此，我们的研究计划的目标是了解HHT疾病的机制，以支持发展有针对性的药物治疗。使用斑马鱼alk1突变体作为HHT2模型，我们发现 AVM发展的两步机制。在步骤1中，流动依赖性Alk1信号传导的丧失增强了内皮细胞在管腔化动脉内流动方向上的迁移。这种异常的迁移内皮细胞分布朝向更远侧动脉段，并扩大更远侧动脉段的口径。在步骤2中，通常扩大的动脉段下游的瞬时动脉-静脉连接以流量依赖性方式保留，导致高流量AVM。在这项工作中，我们将探讨这两个机制的基础独立的基于流动的信号传导途径，其中第一个是废除与Alk1损失，和第二个，其是完整的，但Alk 1损失。在目标1中，我们将结合联合收割机发育生物学和生物力学方法确定血流依赖性Alk1信号传导是否通过控制平面细胞极性或在活斑马鱼胚胎中产生内皮张力。在目标2中，我们将使用斑马鱼胚胎和一种新的微流体平台与人类内皮细胞接种，以剖析的作用，血液流动的两个组成部分-心脏来源的循环ALK 1配体，BMP 10，和机械力，血流中剪切应力和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代表了对改变的血流动力学力的适应性反应，信号传导机制是血流依赖性AVM发展的基础。这些研究将揭示新的光两种不同的血流依赖性途径对HHT相关AVM的发展很重要。机械论从这项工作中收集的信息可以用于开发靶向治疗，1）停止发展，通过修复血流依赖性ALK 1信号传导和正常化内皮细胞迁移，或2）缓慢通过防止现有AVM的血流依赖性扩大来控制表型进展。