Mechanisms underlying myxomatous valve disease

粘液瘤性瓣膜疾病的机制

• 批准号: 10312919
• 负责人: Joshua Waxman
• 金额: $ 54.66万
• 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/10312919
• 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; Lead; Maintenance; Mammals; Methods; Mitral Valve; Mitral Valve Prolapse; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; Myocardial dysfunction; Nature; Neonatal; Operative Surgical Procedures; Orthologous Gene; Pharmacology; Population; Proteins; Regulation; Role; Side; Signal Transduction; Syndrome; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Tretinoin; Tumor-infiltrating immune cells; Vertebrates; Work; Zebrafish; apoAI regulatory protein-1; cardiogenesis; cell type; early onset; effective therapy; extracellular; healing; improved; loss of function; macrophage; mechanotransduction; mortality; mouse model; mutant; neutrophil; novel; older patient; 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.

项目概要/摘要 粘液瘤变性导致二尖瓣脱垂，这种情况发生在普通人群中的近 3% 10%的老年人，是发病和死亡的重要原因。此外，粘液瘤早发型 二尖瓣变性与综合征性疾病和非综合征性疾病相关，支持存在 潜在的遗传病因。尽管二尖瓣疾病很常见，但细胞、分子和遗传因素 二尖瓣粘液瘤变性的病因仍知之甚少。目前，阀门 重建和置换手术是治疗二尖瓣疾病的唯一疗法。因此，在 为了开发能够有效预防和改善二尖瓣病变的新型非侵入性药物疗法 对于瓣膜疾病，了解瓣膜疾病进展的保守机制至关重要 脊椎动物疾病。该提案的具体目标是询问损失的机制 Nr2f 转录因子可导致斑马鱼和小鼠粘液瘤瓣膜的发育。 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，其中一些与粘液瘤性瓣膜变性有关。同时要求 由于 Nr2f 因子在心脏发育中已得到充分证实，之前的工作并未涉及 Nr2f 转录 成熟瓣膜稳态和粘液性瓣膜变性的因素。有趣的是，大多数 先前与粘液瘤性瓣膜变性相关的基因参与细胞外的调节 基质、机械转导和纤毛。我们对成年斑马鱼突变体橡子虫的初步分析 (aco) 缺乏 Nr2f1a，显示它们会发育出具有所有特征的粘液瘤性房室瓣 哺乳动物的粘液瘤瓣膜。此外，我们确定 Nr2f 蛋白在先前表达 房室瓣内未被识别的细胞群。在目标 1 中，我们将使用组织特异性救援 斑马鱼和小鼠的敲除方法以确定瓣膜内皮细胞是否需要 Nr2f 来维持 瓣膜稳态并防止粘液瘤的产生。在目标 2 中，我们将采用药理学和遗传学方法 上位性破译 RA 和包括 Fibrillin 1 在内的信号，其错误表达与粘液瘤相关 人类退化，Nr2f1a 下游功能促进粘液瘤性房室瓣 退化。在目标 3 中，我们将使用谱系追踪和消融研究来确定特定免疫细胞是否 有助于 aco 突变体中粘液瘤性房室瓣的进展。我们利用这些独特的 在小鼠中进行互补分析的突变体将极大地提高我们对保守性的理解 可能导致脊椎动物粘液瘤性瓣膜变性进展的机制。最终，我们的 研究可能为预防和治愈粘液瘤的新型非侵入性疗法提供基础 人类的二尖瓣。