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

• 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
• 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

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，受苦 大约有5,000人中有1人，其特征是动静脉畸形（AVM）的发展。 这些动脉和静脉之间的这些脆弱的直接连接会导致出血，贫血，脑脓肿， 或中风。对于肺，大脑和鼻病变，主要治疗方案是浸润的侵入性程序，可以 切除或阻止流过AVM的流动。肝脏AVM无法安全治疗和严重的肝脏参与， 这可能导致高输出心力衰竭，需要肝移植。 HHT当前的医疗疗法 阻断血管生成或增强凝结，但不靶向疾病机制。因此，我们的目标 研究计划是了解疾病机制，以开发有针对性的医疗疗法 HHT患者。 HHT是由涉及内皮细胞骨的三个基因之一的单倍不足引起的 形态发生蛋白（BMP）信号传导：活化素受体样激酶1（ACVRL1或ALK1），内ognogin（ENG）， 和smad4。因为信号传导约为正常的50％，所以一种治疗方法是增强 途径激活。由肝脏和心脏产生的高度相关的BMP9和BMP10蛋白 在生化上分别被鉴定为ALK1和ENG的高亲和力配体，并且都 在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是可容易的，而两个斑马鱼BMP10 旁系同源物，BMP10和BMP10样，相对于胚胎预防和心脏是多余的 小偷，但已实功能以控制embryonic船舶维护（BMP10）和 心室腔室生长（类似于BMP10）。在AIM 1中，我们将表征青少年的血管和心脏缺陷 - 斑马鱼BMP10突变体。我们假设这些突变体会发展出高输出心力衰竭 继发于血管缺陷，概括HHT患者的疾病进展，并将BMP10牵涉到 一生的关键HHT配体。在AIM 2中，我们将探索心脏的细胞和分子基础 BMP10L突变体胚胎的缺陷，重点是线性心管阶段的发育。在AIM 3中，我们将 使用斑马鱼，细胞培养和生物化学方法来剖析生理和生化基础 embryonic船舶维护中BMP10的具体要求。这些研究将BMP10强调为 对心脏和血管发育和维护的坐标调节的新因素；暗示BMP10 作为基于配体HHT疗法的相关蛋白质；并为理解提供了宝贵的新模型 AVM与高输出心力衰竭之间的机械关系。