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 遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传性血管疾病， 约1/5，000的人，其特征在于动静脉畸形（AVM）的发展。 动脉和静脉之间脆弱的直接连接会导致出血、贫血、脑脓肿， 或者中风对于肺、脑和鼻病变，主要治疗选择是消融的侵入性手术， 切除或阻断通过AVM的血流。肝脏AVM不能安全治疗，严重肝脏受累， 这可能导致高输出量心力衰竭，需要肝脏移植。HHT的当前医学疗法 阻断血管生成或增强凝血，但不靶向疾病机制。因此，我们的目标是 研究计划是了解疾病的机制，以种子发展有针对性的医疗疗法， 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（ACVRL 1，或ALK 1），内皮糖蛋白（ENG）， SMAD4。因为信号传导大约是正常的50%，治疗的一种方法是增强 通路激活由肝脏和心脏产生的高度相关的BMP 9和BMP 10蛋白质， 已被生物化学鉴定为ALK 1和ENG的高亲和力配体， 在血清中检测到蛋白质。为了解决BMP 9和BMP 10作为体内ALK 1配体的要求， 我们培育了斑马鱼突变体。我们发现bmp 9是100，而两条斑马鱼bmp 10 旁系同源物bmp 10和bmp 10样基因在胚胎AVM预防和心脏移植方面是多余的。 小梁形成，但亚功能化，以管理胚胎后血管维持（BMP 10）， 心室生长（类似bmp 10）。在目标1中，我们将描述青少年的血管和心脏缺陷- 到成年斑马鱼BMP 10突变体。我们假设这些突变体发展为高输出量心力衰竭 继发于血管缺陷，重现HHT患者的疾病进展，并涉及BMP 10， 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， bmp 10 l突变胚胎的缺陷，集中在线性心管阶段之后的发育。在目标3中，我们 使用斑马鱼，细胞培养和生物化学方法来解剖生理和生化基础， BMP 10在胚胎后血管维护中的特定需求。这些研究强调BMP 10作为 协调调节心脏和血管发育和维持的新因子;涉及BMP 10 作为基于配体的HHT治疗的相关蛋白质;并为理解 AVM和高输出量心力衰竭之间的机制关系。