Genetic Etiology of Bicuspid Aortic Valve Disease

二叶式主动脉瓣疾病的遗传病因学

基本信息

批准号：
8898893
负责人：
Simon C Body
金额：
$ 39.88万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-23 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898893
关键词：
Accounting Adult Age Aging Animal Model Aortic Diseases Aortic Valve Stenosis Attenuated Benign Bicuspid Biological Assay Biology Blood flow Calcified Cellular biology Clinical Collection Congenital Heart Defects Critical Pathways Development Disease Disease Pathway Disease Progression Dissection Elderly Enrollment Etiology Event Family Family member First Degree Relative Gene Transfer Techniques General Population Genes Genetic Genetic Models Genetic Predisposition to Disease Genotype Goals Heritability Human In Situ Hybridization Incidence Individual Investigation Knock-out Knockout Mice Knowledge Learning Medical Genetics Methods Modeling Molecular Biology Mus Mutation NOTCH1 gene Operative Surgical Procedures Outcome Pathology Pathway interactions Patients Pattern Penetrance Population Predisposition Reporting Research Risk Severity of illness Site Thoracic Aortic Aneurysm Tissues Variant Work Zebrafish abstracting aortic valve aortic valve disorder aortic valve replacement base bicuspid aortic valve calcification cohort exome exome sequencing gene function genome wide association study hemodynamics high throughput screening human disease kindred mouse model non-genetic young adult

项目摘要

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)

描述（由申请人提供）：双质主动脉瓣（BAV）是最常见的先天性心脏畸形，发生在美国人群的0.5-1.2％。超过50％的BAV患者在其一生中出现早期钙化主动脉瓣狭窄或无能，占美国每年在美国进行的> 30,000个主动脉瓣置换术（AVR）的约40％。然而，我们对BAV向主动脉瓣狭窄和无能的病因学，细胞生物学和疾病进展的修饰剂以及胸动脉瘤/解剖的疾病进展几乎一无所知。因此，提出的研究的关键目标是阐明与BAV病理有关的遗传途径。有非常有力的证据表明BAV的遗传力，估计高达89％。在一些家庭中，Notch1的高渗透剂显性突变与BAV有关。还鉴定了额外的敏感性基因座，但未复制。但是，BAV的大多数人都不报告BAV的家庭成员，〜94％的人没有Notch1突变。因此，我们旨在通过利用拥有AVR的BAV患者的多个人群来确定BAV的遗传原因。通过全异位测序和随后的基因分型来鉴定与BAV相关的突变的目的是建立BAV的原因，重要的是，BAV的临床后果基于的遗传背景是基于BAV的遗传背景，从而将研究集中在衰减的途径上，以减轻car钙化瓣膜瓣膜疾病的风险。我们将使用斑马鱼形态模型来模仿已鉴定的人类突变（S），来支持和扩展测序和基因分型努力的发现。我们将尝试使用三种方法来确定影响BAV钙化主动脉瓣疾病进展的遗传和非遗传因素。首先，我们将使用具有钙化主动脉狭窄的AVR的BAV队列来鉴定确定决定的临床和遗传因素主动脉瓣钙化的进展。我们将在已经开发的老化小鼠GATA5敲除模型中研究这些因素。 GATA5敲除小鼠的BAV渗透率为25％，因此可以研究在常见的遗传背景下改变BAV钙化的因素。我们还将使用来自双刺和三尖瓣主动脉瓣的人类钙化主动脉瓣组织的集合来识别这些不同的血液动力学和遗传背景之间的表达差异。我们的整理目的是鉴定双质主动脉瓣疾病的遗传原因及其随后的钙化主动脉狭窄。我们认为，RFA和该提案为攻击BAV钙化主动脉狭窄问题的问题提供了一种可靠，最佳的机制。我们认为，这些方法将允许BAV研究以及患者管理的重要进展。（抽象的结尾）