Molecular mechanisms regulating mouse valvulogenesis

调节小鼠瓣膜发生的分子机制

• 批准号: 8931798
• 负责人: KAI JIAO
• 金额: $ 7.17万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931798
• 关键词: 3' Untranslated Regions; Abbreviations; Accounting; Alleles; Anabolism; Animals; Biological; Biological Assay; Biological Models; Birth; Cardiovascular Diseases; Cells; Clinical; Collagen; Complement; Complex; Congenital Abnormality; Defect; Developed Countries; Development; Diagnostic; Disease; Embryo; Gel; Gene Expression Regulation; Generations; Genes; Goals; Heart Valves; Human; Hyperplasia; Knowledge; Lead; Mammals; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Genetics; Mus; Mutation; Neonatal; Newborn Infant; Noonan Syndrome; PTPN11 gene; Pathologic Processes; Pathway interactions; Patients; Play; Publications; Reagent; Repression; Research; Research Design; Ribonuclease III; Role; Site; Stenosis; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Zebrafish; clinical application; congenital heart disorder; gain of function mutation; infant morbidity/mortality; malformation; mouse model; mutant; prevent; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Congenital heart diseases (CHDs) are the most common form of birth defects, occurring in as many as 1-5% of newborns, and remain the leading noninfectious cause of infant morbidity and mortality in developed countries. Malformation of valves accounts for up to 30% of CHDs. Despite decades of research, the mechanisms underlying congenital valve diseases remain largely elusive. MicroRNAs (miRNAs) have emerged as promising therapeutic targets/agents for various cardiovascular diseases. While critical roles of miRNAs in regulating cardiomyogenesis have been well established, their activities during valvulogenesis, especially in mammals, have been barely studied. Our current knowledge of miRNA function in developing valves is limited to several publications using zebrafish as the primary model system. The lack of knowledge regarding the roles of miRNAs during mammalian valvulogenesis poses a major barrier to developing diagnostic/therapeutic applications for miRNAs against valve diseases. To directly test whether miRNAs are essential for mammalian valve development, we established a mouse model in which Dicer1 is specifically inactivated in embryonic endocardial cells, which are precursors of valve leaflet cells. Our studies reveal for the first time that the miRNA regulatory machinery in endocardial cells is required for normal valvulogenesis to support survival of neonatal mice. We propose the central hypothesis that miRNAs are essential components of the molecular regulatory network governing normal valvulogenesis in mammals. We will test this hypothesis through the following two Specific Aims. In Aim 1, we will determine the effect of globally blocking miRNA biosynthesis in endocardial cells on valvulogenesis in mice. In Aim 2, we will test the role of miRNA-mediated repression of Ptpn11 in preventing valve hyperplasia. MiRNAs play important roles in numerous biological/pathological processes, and yet their functions during mammalian valvulogenesis have not been examined. Accomplishing these studies will significantly advance our fundamental understanding of the complex molecular/genetic mechanisms regulating mammalian valvulogenesis and provide crucial clues regarding the use of miRNAs for clinical applications against congenital valve diseases.

描述（由申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷形式，发生在多达1-5%的新生儿中，并且仍然是发达国家婴儿发病率和死亡率的主要非感染性原因。瓣膜畸形占CHD的30%。尽管经过数十年的研究，先天性瓣膜疾病的潜在机制仍然很难理解。 微小RNA（miRNAs）已经成为各种心血管疾病的有希望的治疗靶标/药剂。虽然miRNAs在调节心肌发生中的关键作用已经得到很好的确立，但它们在瓣膜发生中的活性，特别是在哺乳动物中，几乎没有研究。我们目前对miRNA在瓣膜发育中的功能的了解仅限于几篇使用斑马鱼作为主要模型系统的出版物。对miRNAs在哺乳动物瓣膜发生过程中的作用的了解的缺乏对开发miRNAs针对瓣膜疾病的诊断/治疗应用构成了主要障碍。 为了直接测试miRNAs是否是哺乳动物瓣膜发育所必需的，我们建立了一个小鼠模型，其中Dicer 1在胚胎内皮细胞中特异性失活，胚胎内皮细胞是瓣膜小叶细胞的前体。我们的研究首次揭示了内皮细胞中的miRNA调控机制是正常瓣膜发生所必需的，以支持新生小鼠的存活。我们提出的核心假设是，miRNA是控制哺乳动物正常瓣膜发生的分子调控网络的重要组成部分。我们将通过以下两个具体目标来检验这一假设。在目标1中，我们将确定全面阻断内皮细胞中miRNA生物合成对小鼠瓣膜发生的影响。在目标2中，我们将测试miRNA介导的Ptpn 11抑制在预防瓣膜增生中的作用。 miRNAs在许多生物学/病理学过程中发挥重要作用，但它们在哺乳动物瓣膜发生过程中的功能尚未得到研究。完成这些研究将显著推进我们对调节哺乳动物瓣膜发生的复杂分子/遗传机制的基本理解，并提供关于使用miRNA用于临床应用以对抗先天性瓣膜疾病的关键线索。