Genetic Etiology of Bicuspid Aortic Valve Disease

描述（由申请人提供）： 二叶式主动脉瓣（BAV）是最常见的先天性心脏畸形，在美国人群中的发生率为0.5-1.2%。超过50%的BAV患者在其一生中发生早期钙化性主动脉瓣狭窄或关闭不全，占美国每年进行的> 30，000例主动脉瓣置换术（AVR）的约40%。然而，我们对BAV至主动脉瓣狭窄和关闭不全以及胸主动脉瘤/夹层的病因学、细胞生物学和疾病进展的修饰因子知之甚少。因此，拟定研究的一个关键目标是阐明BAV病理学中涉及的遗传途径。有非常有力的证据表明BAV的遗传性，估计高达89%。在少数家族中，NOTCH 1的高度显性突变与BAV相关。其他易感基因座也已确定，但没有复制。然而，大多数患有BAV的个体没有报告患有BAV的家庭成员，并且约94%不具有NOTCH 1突变。因此，我们的目标是通过使用多个BAV患者队列（已接受和未接受AVR）来确定BAV的遗传原因。通过全外显子组测序和随后的基因分型鉴定BAV相关突变的目的是确定BAV的病因，重要的是，确定BAV临床后果所基于的遗传背景，从而将研究重点放在降低成年期钙化性主动脉瓣疾病风险的途径上。我们将通过研究BAV的胚胎学分子生物学来支持和扩展测序和基因分型工作的发现，使用斑马鱼吗啉代模型来模拟已鉴定的人类突变。我们将尝试使用三种方法确定影响BAV钙化主动脉瓣疾病进展的遗传和非遗传因素。首先，我们将使用已经和尚未接受主动脉瓣置换术治疗钙化性主动脉瓣狭窄的BAV队列，以确定决定性的临床和遗传因素。 主动脉瓣钙化进展。我们将在一个已经建立的衰老小鼠GATA 5基因敲除模型中研究这些因素。GATA 5基因敲除小鼠具有25%的BAV钙化率，因此允许研究在共同遗传背景下改变BAV钙化的因素。我们还将使用来自二叶和三叶主动脉瓣的人类钙化主动脉瓣组织的集合来鉴定这些不同的血液动力学和遗传背景之间的表达差异。我们的主要目的是确定二叶式主动脉瓣疾病及其继发的钙化性主动脉瓣狭窄的遗传原因。我们认为，RFA和该提案为BAV治疗钙化性主动脉瓣狭窄问题提供了可靠和最佳的机制。我们相信这些方法将使BAV研究和潜在的患者管理取得重大进展。 (End摘要）

DESCRIPTION (provided by applicant): Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation, occurring in 0.5-1.2% of the US population. Over 50% of patients with BAV develop early calcific aortic valve stenosis or incompetence in their lifetime and accounts for ~40% of the >30,000 aortic valve replacements (AVRs) performed in the US each year. Yet, we know little of the etiology, cellular biology and modifiers of disease progression for BAV to aortic valve stenosis and incompetence, and thoracic aortic aneurysm/dissection. Therefore, a critical goal of the proposed studies is to elucidate the genetic pathways involved in BAV pathology. There is very strong evidence for heritability of BAV, with estimates as high as 89%. In a few families, highly-penetrant dominant mutations of NOTCH1 have been associated with BAV. Additional susceptibility loci have also been identified but not replicated. However, a majority of individual with BAV do not report family members with BAV and ~94% do not possess a NOTCH1 mutation. We therefore aim to identify the genetic cause(s) of BAV by utilizing multiple cohorts of individuals with BAV who have, and have not, undergone AVR. The purpose of identifying BAV-associated mutations by whole-exome sequencing and subsequent genotyping is to establish the cause of BAV and importantly, the genetic background on which the clinical consequences of BAV are based, thus focusing research on pathways to attenuate the risk of calcific aortic valve disease in adulthood. We will support and expand the findings of sequencing and genotyping efforts by investigating the embryologic molecular biology of BAV, using Zebrafish morpholino models to mimic the identified human mutation(s). We will to attempt to identify genetic and non-genetic factors that impact on the progression of BAV calcific aortic valve disease using three methods. First, we will use BAV cohorts who have, and have not yet, undergone AVR for calcific aortic stenosis, to identify clinical and genetic factors that determine progression of aortic valve calcification. We will investigate these factors in an already-developed aging mouse GATA5 knockout model. The GATA5 knockout mouse has a 25% BAV penetrance, thus allowing investigation of the factors that alter calcification of the BAV on a common genetic background. We will also use a collection of human calcified aortic valve tissue from bicuspid and tricuspid aortic valves to identify expression differences between these different hemodynamic and genetic backgrounds. Our over-arching purpose is identification of genetic causes of bicuspid aortic valve disease and its subsequent calcific aortic stenosis. We believe that the RFA and this proposal provide a credible and best mechanism for attacking the issue of calcific aortic stenosis with BAV. We believe these methods will allow for critical advances in BAV research and potentially, patient management. (End of Abstract)