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.

项目摘要/摘要 粘液瘤样变性导致二尖瓣脱垂，约占总人口的3%。 和10%的老年人，是发病率和死亡率的重要原因。此外，早发性粘液瘤 二尖瓣退行性变既与综合征性疾病有关，也与非综合征性疾病有关，支持有 潜在的遗传病因学。尽管二尖瓣疾病的频率很高，但细胞、分子和遗传因素 二尖瓣粘液瘤样变性的病因尚不清楚。目前，阀门 重建和置换手术是治疗二尖瓣疾病的唯一方法。因此，在 为开发有效预防和改善二尖瓣病变的新型非侵入性药物 对于瓣膜疾病，了解瓣膜进展的保守机制是至关重要的。 脊椎动物中的疾病。这项提议的具体目的是询问造成损失的机制 Nr2f转录因子可导致斑马鱼和小鼠的粘液瘤瓣膜发育。 大量研究表明，人类Nr2f基因突变与一系列 先天性心脏缺陷，其中一些与粘液瘤性瓣膜变性有关。虽然要求 由于Nr2f因子在心脏发育中得到了很好的证实，以前的工作并没有涉及Nr2f转录 影响成熟瓣膜动态平衡和粘液瘤性瓣膜退变的因素。有趣的是，大多数人 先前与粘液瘤性瓣膜变性相关的基因参与了细胞外的调节 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，表明他们发展为粘液瘤房室瓣膜，具有所有特征 哺乳动物的粘液瘤瓣膜。此外，我们还鉴定了Nr2f蛋白在以前的 房室瓣膜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 斑马鱼和小鼠的基因敲除方法确定瓣膜内皮细胞是否需要Nr2f来维持 瓣膜动态平衡和防止粘液瘤的产生。在目标2中，我们将使用药理学和遗传学 破译类风湿性关节炎和包括纤维蛋白1在内的信号的上位性，其错误表达与粘液瘤相关 人类退行性变，Nr2f1a下游功能促进粘液瘤房室瓣 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 在ACO突变型粘液瘤型房室瓣的进展中起重要作用。我们使用这些独特的 在小鼠身上进行互补分析的突变体将极大地提高我们对保守序列的理解 可导致脊椎动物粘液瘤瓣膜退行性变的机制。最终，我们的 研究可能为预防和治愈粘液瘤的新的非侵入性疗法提供基础 人类的二尖瓣。