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

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.

项目总结/摘要 粘液瘤变性导致二尖瓣脱垂，发生在几乎3%的一般人群中 和10%的老年人，是发病率和死亡率的重要原因。此外，粘液瘤性的早发性 二尖瓣退行性变与综合征和非综合征疾病相关，支持存在 潜在的遗传病因学尽管二尖瓣疾病的频率，细胞，分子和遗传 二尖瓣粘液瘤变性的病因仍然知之甚少。目前，阀门 重建和置换手术是二尖瓣疾病唯一可用的治疗方法。因此在 为了开发新的非侵入性药物治疗，可以有效地预防和改善二尖瓣 瓣膜疾病，了解瓣膜疾病进展的保守机制是至关重要的。 脊椎动物的疾病这项建议的具体目的是要探讨造成损失的机制， Nr 2f转录因子可导致斑马鱼和小鼠粘液瘤样瓣膜的发育。 许多研究表明，人类Nr 2f基因的突变与一系列疾病相关。 先天性心脏缺陷，其中一些与粘液瘤性瓣膜变性有关。虽然所需经费 由于Nr 2f因子在心脏发育中已得到充分证实，以前的工作并未涉及Nr 2f转录 成熟瓣膜和粘液瘤性瓣膜变性的稳态因子。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基质的调节， 基质、机械转导和纤毛。我们对成年斑马鱼橡子虫突变体的初步分析 (aco)缺乏Nr 2f 1a的患者，显示他们发展出具有所有特征的粘液瘤性房室瓣。 粘液瘤瓣膜的组织结构。此外，我们还鉴定了Nr 2f蛋白在以前的细胞中表达， 房室瓣内未识别的细胞群。在目标1中，我们将使用组织特异性拯救 以及斑马鱼和小鼠中的敲除方法，以确定瓣膜内皮细胞是否需要Nr 2f来维持 瓣膜稳态和防止粘液瘤的产生。在目标2中，我们将采用药理学和遗传学方法， 上位性来解读RA和包括原纤蛋白1的信号，其错误表达与粘液瘤相关， 在人类中，Nr 2f 1a的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的免疫细胞是否 有助于ACO突变体中粘液瘤性房室瓣的进展。我们使用这些独特的 在小鼠中进行互补分析的突变体将大大提高我们对保守的 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 研究可能为新型非侵入性治疗提供基础， 人类的二尖瓣