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BIOMECHANICAL FACTORS IN CONGENITAL VASCULAR DISEASE

先天性血管疾病的生物力学因素

基本信息

批准号：
8833325
负责人：
Jessica Wagenseil
金额：
$ 37.43万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-13 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8833325
关键词：
5 year old Adverse effects Affect Age-Years Aneurysm Antihypertensive Agents Aorta Biomechanics Birth Blood Pressure Blood Vessels Blood flow Cells Coarctation of the aorta Congenital Abnormality Defect Development Diagnosis Disease Distal Elastic Fiber Elasticity Elastin Embryo Embryonic Development Environment Extracellular Matrix Gene Expression Gene Targeting Genes Genetic Geometry Goals Human Infant Knock-out Lead Measures Mechanics Mouse Strains Mus Operative Surgical Procedures Pathology Pathway interactions Perinatal Pharmacologic Substance Phenotype Property Protein-Lysine 6-Oxidase Proteins Repeat Surgery Research Signal Transduction Site Smooth Muscle Myocytes Stress Supravalvular aortic stenosis Testing Time Vascular Diseases arterial remodeling blood pressure reduction critical period crosslink fibulin-4 genetic approach heart function hemodynamics human disease improved mechanical behavior mortality mouse development mouse model new therapeutic target novel prevent response

项目摘要

DESCRIPTION (provided by applicant): Coarctation of the aorta (COA) is the most common congenital vascular defect. It is characterized by local narrowing of the aorta and treatment is recommended by 5 years of age. Supravalvular aortic stenosis (SVAS) is a less common congenital defect that is also characterized by local aortic narrowing. About 60% of infants diagnosed with SVAS require surgical intervention to improve heart function. Complications of COA and SVAS treatment include operative mortality, aneurysms and recoarctation requiring reoperation. In both COA and SVAS, elastic fiber fragmentation suggests that elasticity and mechanical properties of the wall may be important for disease pathology. The mechanical properties of the wall and the hemodynamic forces, blood pressure and blood flow, change significantly in late embryonic development when the arterial narrowing occurs. The proposed research will test the hypothesize that arterial narrowing is caused by altered smooth muscle cell (SMC) phenotype in response to changes in the mechanical environment during late embryonic development. The proposed research will also determine if arterial narrowing can be prevented by changing the mechanical environment during targeted developmental periods through alterations in arterial elasticity or reduced blood pressure. The hypothesis will be tested using genetically-modified mice and pharmaceutical treatments. Three mouse models with reduced arterial elasticity caused by knockouts of different proteins, elastin (Eln), fibulin-4 (Fbln4) and lysyl oxidase (Lox) will be used. Elastin is the primary component of elastic fibers in the arterial wall; fibulin-4 is necessary for proper assembly of the elastic fibers; and lysyl oxidse crosslinks the soluble form of elastin into its mechanically functional form. All three mouse lines are perinatal lethal and show local aortic narrowing, but the mechanical environment has not been characterized. Two conditional mouse lines that turn elastin on or off during late embryonic development will also be used to determine if changing the arterial elasticity minimizes, prevents or delays narrowing. Lastly, established anti- hypertensive drugs will be used to reduce blood pressure during late embryonic development and determine if reducing the hemodynamic stress on the SMCs minimizes, prevents or delays arterial narrowing. In all cases, blood pressure, blood flow and arterial mechanical properties will be measured to quantify the mechanical environment. Ultrastructural studies and targeted gene array analysis will determine how the mechanical environment affects the extracellular matrix (ECM) and SMC phenotype. These studies will be important for identifying the mechanical and genetic pathways that lead to arterial narrowing in diseases such as COA and SVAS and will test preventative treatments.

描述（由申请人提供）：主动脉缩窄（COA）是最常见的先天性血管缺陷。它的特点是局部狭窄的主动脉和治疗建议由5岁。主动脉瓣上狭窄（SVAS）是一种不太常见的先天性缺陷，其特征也是局部主动脉狭窄。大约60%的SVAS婴儿需要手术干预以改善心脏功能。COA和SVAS治疗的并发症包括手术死亡率、动脉瘤和需要再次手术的再缩窄。在COA和SVAS中，弹性纤维断裂表明壁的弹性和机械性质对疾病病理学可能是重要的。当动脉狭窄发生时，壁的机械性质和血液动力学力、血压和血流量在胚胎发育后期发生显著变化。拟议的研究将测试动脉狭窄是由平滑肌细胞（SMC）表型改变引起的假设，以响应胚胎发育后期机械环境的变化。拟议的研究还将确定是否可以通过改变动脉弹性或降低血压来改变目标发育期的机械环境来预防动脉狭窄。假设将被检验使用转基因小鼠和药物治疗。将使用三种小鼠模型，其具有由不同蛋白质（弹性蛋白（Eln）、纤蛋白-4（Fbln 4）和赖氨酰氧化酶（Lox））的敲除引起的动脉弹性降低。弹性蛋白是人体内弹性纤维的主要成分，动脉壁;纤蛋白-4对于弹性纤维的正确组装是必需的;赖氨酰氧化酶将弹性蛋白的可溶形式交联成其机械功能形式。所有三条鼠标线是围产期致死性的，并显示局部主动脉狭窄，但机械环境尚未得到表征。在胚胎发育后期打开或关闭弹性蛋白的两个条件性小鼠系也将用于确定改变动脉弹性是否最大限度地减少、防止或延迟狭窄。最后，已确定的抗高血压药物将用于在胚胎发育后期降低血压，并确定降低SMC上的血流动力学应力是否最大限度地减少、预防或延迟动脉狭窄。在所有情况下，将测量血压、血流量和动脉机械特性，以量化机械环境。超微结构研究和靶向基因阵列分析将确定机械环境如何影响细胞外基质（ECM）和SMC表型。这些研究对于确定导致动脉粥样硬化的机械和遗传途径非常重要。缩小疾病，如COA和SVAS，并将测试预防性治疗。