BMP10 IN CARDIOVASCULAR DEVELOPMENT AND HEREDITARY HEMORRHAGIC TELANGIECTASIA

BMP10 在心血管发育和遗传性出血性毛细血管扩张症中的作用

基本信息

批准号：
9156157
负责人：
BETH L ROMAN
金额：
$ 39.71万
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：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9156157
关键词：
ACVRL1 gene Ablation Address Adolescent Adult Affinity Age Agreement Anemia Apical Arteries Arteriovenous malformation BMP10 gene Benefits and Risks Biochemical Biochemistry Blood Circulation Blood Vessels Bone Morphogenetic Proteins Brain Brain Abscess Cardiac Cardiovascular Physiology Cardiovascular system Cell Communication Cell Culture Techniques Cell Surface Proteins Coagulation Process Defect Development Disease Disease Progression Down-Regulation Embryo Endocardium Endoglin Endothelial Cells Erythema Excision Family Fibrinolytic Agents Genes Goals Growth Heart Heart Abnormalities Heart failure Hemorrhage Hereditary Disease Hereditary hemorrhagic telangiectasia Human Intervention Knockout Mice Laboratories Lasers Lead Learning Life Ligands Liver Lung MADH4 gene Maintenance Mammals Mediating Medical Medicine Methods Modeling Molecular Mus Myocardium Nature Nose Operative Surgical Procedures Organ Output Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Pregnancy Prevention Primary Lesion Procedures Proteins Regulation Research Resected Risk Role Secondary to Seeds Serum Signal Transduction Site Skin Specificity Staging Stroke Structure of mucous membrane of nose Surface Testing Therapeutic Embolization Transforming Growth Factor beta Tube Vascular Diseases Vascular resistance Veins Ventricular Visceral Zebrafish activin receptor-like kinase 1 angiogenesis base cell type effective therapy in vivo liver transplantation malformation mutant novel paralogous gene prevent programs receptor targeted treatment vascular abnormality

项目摘要

PROJECT SUMMARY Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, afflicting approximately 1 in 5,000 people, that is characterized by development of arteriovenous malformations (AVMs). These fragile, direct connections between arteries and veins can lead to hemorrhage, anemia, brain abscess, or stroke. For lung, brain, and nasal lesions, the primary treatment options are invasive procedures that ablate, resect, or block flow through the AVM. Liver AVMs cannot be safely treated and severe liver involvement, which can lead to high-output heart failure, requires liver transplantation. Current medical therapies for HHT block angiogenesis or enhance clotting but do not target disease mechanism. As such, the goal of our research program is to understand disease mechanism to seed development of targeted medical therapies for HHT patients. HHT is caused by haploinsufficiency of one of three genes involved in endothelial cell bone morphogenetic protein (BMP) signaling: activin receptor-like kinase 1 (ACVRL1, or ALK1), endoglin (ENG), and SMAD4. Because signaling is approximately 50% of normal, one approach to therapy is to enhance pathway activation. The highly related BMP9 and BMP10 proteins, produced by the liver and heart, respectively, have been biochemically identified as high affinity ligands for both ALK1 and ENG, and both proteins are detected in serum. To address the requirements for BMP9 and BMP10 as ALK1 ligands in vivo, we generated zebrafish mutants. We found that bmp9 is dispensable, whereas the two zebrafish bmp10 paralogs, bmp10 and bmp10-like, are redundant with respect to embryonic AVM prevention and cardiac trabeculation, but have subfunctionalized to govern post-embryonic vessel maintenance (bmp10) and ventricular chamber growth (bmp10-like). In Aim 1, we will characterize vascular and heart defects in juvenile- to-adult zebrafish bmp10 mutants. We hypothesize that these mutants develop high output heart failure secondary to vascular defects, recapitulating disease progression in HHT patients and implicating BMP10 as the critical HHT ligand throughout life. In Aim 2, we will explore the cellular and molecular basis of heart defects in bmp10l mutant embryos, focusing on development after the linear heart tube stage. In Aim 3, we will use zebrafish, cell culture, and biochemistry approaches to dissect the physiological and biochemical basis for the specific requirement for BMP10 in post-embryonic vessel maintenance. These studies highlight BMP10 as a novel factor in the coordinate regulation of heart and vessel development and maintenance; implicate BMP10 as the relevant protein for ligand-based HHT therapy; and provide an invaluable new model for understanding the mechanistic relationship between AVMs and high-output heart failure.

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，大约五千分之一的人患有动静脉畸形 (AVM)。动脉和静脉之间这些脆弱的直接连接可能导致出血、贫血、脑脓肿、或中风。对于肺、脑和鼻部病变，主要的治疗选择是侵入性手术，消融、切除或阻断流过 AVM 的血流。肝脏动静脉畸形无法安全治疗且肝脏严重受累，这可能导致高输出量心力衰竭，需要肝移植。目前 HHT 的药物治疗阻断血管生成或增强凝血，但不针对疾病机制。因此，我们的目标研究计划的目的是了解疾病机制，以开发靶向药物疗法 HHT 患者。 HHT 是由参与内皮细胞骨的三个基因之一的单倍体不足引起的形态发生蛋白 (BMP) 信号传导：激活素受体样激酶 1（ACVRL1 或 ALK1）、内皮糖蛋白 (ENG)、和 SMAD4。由于信号传导约为正常信号的 50%，因此一种治疗方法是增强通路激活。高度相关的 BMP9 和 BMP10 蛋白由肝脏和心脏产生，分别已被生化鉴定为 ALK1 和 ENG 的高亲和力配体，并且两者均血清中检测到蛋白质。为了满足 BMP9 和 BMP10 作为体内 ALK1 配体的要求，我们产生了斑马鱼突变体。我们发现bmp9是可有可无的，而斑马鱼的两个bmp10 旁系同源物（bmp10 和 bmp10 样）对于胚胎 AVM 预防和心脏病来说是多余的小梁形成，但已亚功能化以管理胚胎后血管维护（bmp10）和心室生长（bmp10 样）。在目标 1 中，我们将描述青少年血管和心脏缺陷的特征。至成年斑马鱼 bmp10 突变体。我们假设这些突变体会发展为高输出量心力衰竭继发于血管缺陷，概括了 HHT 患者的疾病进展并暗示 BMP10 整个生命过程中关键的 HHT 配体。在目标 2 中，我们将探索心脏的细胞和分子基础 bmp10l 突变体胚胎中的缺陷，重点关注线性心管阶段后的发育。在目标 3 中，我们将使用斑马鱼、细胞培养和生物化学方法来剖析其生理和生化基础 BMP10 在胚胎后血管维护中的具体要求。这些研究强调 BMP10 作为协调调节心脏和血管发育和维护的新因素；牵涉BMP10 作为基于配体的 HHT 疗法的相关蛋白；并提供一个宝贵的新模型来理解 AVM 与高输出量心力衰竭之间的机制关系。