Mechanisms underlying myxomatous valve disease

粘液瘤性瓣膜疾病的机制

• 批准号: 10611524
• 负责人: Joshua Waxman
• 金额: $ 52.34万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611524
• 关键词: Ablation; Adult; Affect; Alleles; Cardiac Surgery procedures; Cause of Death; Cells; Cessation of life; Child; Cilia; Collagen Fiber; Congenital Heart Defects; Coupled; Data; Deposition; Development; Disease; Elderly; Embryo; Endothelial Cells; Environment; Exhibits; Extracellular Matrix; FBN1; Foundations; Frequencies; General Population; Generations; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Glycosaminoglycans; Heart; Heart Abnormalities; Homeostasis; Human; Immune; Infiltration; Knock-out; Knockout Mice; Macrophage; Maintenance; Mammals; Methods; Mitral Valve; Mitral Valve Prolapse; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myocardial dysfunction; Nature; Neonatal; Operative Surgical Procedures; Orthologous Gene; Population; Proteins; Regulation; Role; Side; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Tretinoin; Vertebrates; Work; Zebrafish; apoAI regulatory protein-1; cardiogenesis; cell type; early onset; effective therapy; extracellular; healing; immune cell infiltrate; improved; loss of function; mechanotransduction; mortality; mouse model; mutant; neutrophil; novel; older patient; pharmacologic; postnatal; prevent; reconstruction; single-cell RNA sequencing; transcription factor; transcriptome sequencing; transcriptomics; valve replacement; Ablation; Adult; Affect; Alleles; Cardiac Surgery procedures; Cause of Death; Cells; Cessation of life; Child; Cilia; Collagen Fiber; Congenital Heart Defects; Coupled; Data; Deposition; Development; Disease; Elderly; Embryo; Endothelial Cells; Environment; Exhibits; Extracellular Matrix; FBN1; Foundations; Frequencies; General Population; Generations; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Glycosaminoglycans; Heart; Heart Abnormalities; Homeostasis; Human; Immune; Infiltration; Knock-out; Knockout Mice; Macrophage; Maintenance; Mammals; Methods; Mitral Valve; Mitral Valve Prolapse; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myocardial dysfunction; Nature; Neonatal; Operative Surgical Procedures; Orthologous Gene; Population; Proteins; Regulation; Role; Side; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Tretinoin; Vertebrates; Work; Zebrafish; apoAI regulatory protein-1; cardiogenesis; cell type; early onset; effective therapy; extracellular; healing; immune cell infiltrate; improved; loss of function; mechanotransduction; mortality; mouse model; mutant; neutrophil; novel; older patient; pharmacologic; postnatal; prevent; reconstruction; single-cell RNA sequencing; transcription factor; transcriptome sequencing; transcriptomics; valve replacement

Project Summary/Abstract Myxomatous degeneration leads to mitral valve prolapse, which occurs in almost 3% of the general population and 10% of the elderly, is a significant cause of morbidity and mortality. Additionally, early-onset of myxomatous mitral valve degeneration is associated with both syndromic and non-syndromic diseases, supporting there is an underlying genetic etiology. Despite the frequency of mitral valve diseases, the cellular, molecular, and genetic etiologies underlying myxomatous degeneration of the mitral valves remain poorly understood. Presently, valve reconstruction and replacement surgeries are the only therapies available for mitral valve diseases. Thus, in order to develop novel non-invasive pharmacological therapies that can effectively prevent and ameliorate mitral valve diseases, it is essential to understand conserved mechanisms the underlie the progression of valve diseases in vertebrates. The specific aims of this proposal are to interrogate the mechanisms by which loss of the Nr2f transcription factors can lead to the development of myxomatous valves in zebrafish and mice. Numerous studies have indicated that mutations in Nr2f genes in humans are associated with a spectrum of congenital heart defects, some of which are correlated with myxomatous valve degeneration. While requirements for Nr2f factors are well-established in heart development, previous work has not implicated Nr2f transcription factors in homeostasis of mature valves and myxomatous valve degeneration. Interestingly, the majority of previous genes associated with myxomatous valve degeneration are involved in the regulation of extracellular matrix, mechanotransduction, and cilia. Our preliminary analysis in adult zebrafish mutants called acorn worm (aco), which are deficient for Nr2f1a, show they develop myxomatous atrioventricular valves with all the hallmarks of myxomatous valves in mammals. Furthermore, we identify Nr2f proteins are expressed in previously unrecognized populations of cells within the atrioventricular valves. In Aim 1, we will use tissue-specific rescue and knockout approaches in zebrafish and mice to determine if valve endothelial cells require Nr2f to maintain valve homeostasis and prevent myxomatous generation. In Aim 2, we will employ pharmacological and genetic epistasis to decipher if RA and signals including Fibrillin 1, whose misexpression is associated with myxomatous degeneration in humans, function downstream of Nr2f1a to promote myxomatous atrioventricular valve degeneration. In Aim 3, we will use lineage tracing and ablation studies to determine if specific immune cells contribute to the progression of myxomatous atrioventricular valves in aco mutants. Our use of these unique mutants with complementary analysis in mice will dramatically improve our understanding of conserved mechanisms that can lead to the progression of myxomatous valve degeneration in vertebrates. Ultimately, our studies may provide the foundation for novel non-invasive therapies that can prevent and heal myxomatous mitral valves in humans.

项目摘要/摘要 菌丝变性导致二尖瓣脱垂，几乎3％的一般人群发生 10％的老年人是发病率和死亡率的重要原因。另外，霉菌的早期发作 二尖瓣变性与综合症和非综合性疾病有关，支持存在 潜在的遗传病因。尽管二尖瓣疾病发生频率，但细胞，分子和遗传 二尖瓣的粘液性变性为基础的病因仍然鲜为人知。目前，阀门 重建和置换手术是二尖瓣疾病的唯一疗法。因此，在 为了开发可有效预防和改善二尖瓣的新型非侵入性药理学疗法 瓣膜疾病，必须了解保守机制的基础阀的进展是至关重要的 脊椎动物中的疾病。该提案的具体目的是审问损失损失的机制 NR2F转录因子可能导致斑马鱼和小鼠中粘液瓣的发展。 大量研究表明，人类NR2F基因的突变与一系列 先天性心脏缺陷，其中一些与粘液瓣变性有关。而要求 因为NR2F因素在心脏发展中已经建立了良好 成熟瓣膜和粘液瓣变性的稳态因素。有趣的是，大多数 先前与粘液瓣变性相关的基因参与细胞外的调节 基质，机械转导和纤毛。我们在成年斑马鱼突变体中的初步分析称为橡子蠕虫 （ACO）缺乏NR2F1A，表明它们具有所有标志 哺乳动物中的粘液瓣。此外，我们识别NR2F蛋白在先前表达 房屋内瓣膜内未识别的细胞群体。在AIM 1中，我们将使用组织特定的救援 斑马鱼和小鼠的敲除方法，以确定阀内皮细胞是否需要NR2F维持 瓣膜稳态并预防粘液瘤产生。在AIM 2中，我们将采用药理学和遗传 上学将解密的话，如果RA和包括原纤维蛋白1的信号，其Misexpression与粘液瘤相关 人类的变性，NR2F1A下游的功能以促进粘液室室内瓣膜 退化。在AIM 3中，我们将使用谱系跟踪和消融研究来确定特定的免疫细胞是否是否 有助于ACO突变体中粒细胞护心瓣的进展。我们对这些独特的使用 在小鼠中进行互补分析的突变体将极大地改善我们对保守的理解 可能导致脊椎动物中粘液瓣变性进展的机制。最终，我们的 研究可能为可以预防和治愈粘液的新型非侵入性疗法提供基础 人类的二尖瓣。