Nkx2-5 and congenital heart defects in Xenopus

Nkx2-5 与爪蟾先天性心脏缺陷

• 批准号: 8269765
• 负责人: DANIEL L. WEEKS
• 金额: $ 31.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269765
• 关键词: Address; Affect; Back; Biological Assay; Cardiac; Cells; Characteristics; Chickens; Chordata; Chromatin Structure; Congenital Heart Defects; Connective Tissue; Defect; Development; Developmental Process; Dorsal; Drosophila genus; Embryo; Endothelium; Family member; Fishes; Galium; Genes; Genetic; Growth; Handedness; Health; Heart; Heart Atrium; Heart Valves; Homologous Gene; Human; Intervention; Maintenance; Maps; Mediating; Modeling; Molecular; Mus; Muscle; Mutation; Myocardial Contraction; Newborn Infant; Nucleic Acid Regulatory Sequences; Oligonucleotides; Organism; Pathway interactions; Pattern; Pluripotent Stem Cells; Protein Biosynthesis; Protein Family; Proteins; Rana; Regulation; Regulatory Pathway; Reporter; Rest; Role; Series; Sparrows; Stem cells; Structural Protein; System; TAC1 gene; Tachycardia; Tertiary Protein Structure; Transcript; Vascular System; Ventricular; Vertebrates; Work; Xenopus; Xenopus laevis; blastomere structure; blood pump; cardiogenesis; cell type; congenital heart disorder; falls; fly; genetic regulatory protein; heart dimension/size; loss of function; mRNA Transcript Degradation; man; null mutation; pluripotency; prevent; programs; promoter; protein expression; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): The formation of a normal heart requires the tightly regulated activation of a series of genes. This regulation begins early in development as cells progressively lose pluripotency and settle into lineages that result in muscle, endothelium, valves and the connective tissue of the heart. Defining the appropriate lineages is important, but equally important is the modeling of these different cell types into the chambers, valves, septae and conduction system that form a working heart. Among the regulators of the cardiac developmental program are transcription factors from NK-2 family of proteins. First identified in fruit fly as the gene called tinman (because the null mutation gave rise to flies that failed to form a dorsal vessel (the fly's heart)) we now refer to the homologue in man and other chordates as Nkx2-5. Humans with mutations in even one of their copies of Nkx2-5 develop congenital heart defects. Among their problems are malformed septae that separate the chambers of the heart, heart valve defects and abnormal regulation of heart contraction. Recently, mutations in a related protein Nkx2-6, was shown to cause problems in the outflow tract of the heart, the region that connects the blood pumped by the heart back into the vascular system. The NK-2 genes involved in heart formation have been studied to good advantage in a variety of system, including mouse, chicken, fly, fish and the frog Xenopus laevis. The regulatory division of labor in frog falls to three members of this family, Nkx2-5, Nkx2-3 and Nkx2-10 (the likely homologue of human Nkx2-6). We propose experiments to track the role of each of these transcription factors during early cardiac development, define the protein domains of each that confer unique function and identify how the expression of each is regulated. This will allow us to separate the regulatory pathways that must be coordinated to form a working heart. PUBLIC HEALTH RELEVANCE: Congenital heart defects in human affect 1% of all newborns, and present a persistent health challenge for the rest of their lives. One of the genetic causes of congenital heart defects are mutations in the transcription factors Nkx2-5, and Nkx2-6 that leads to the misregulation of genes needed for correct heart formation. These studies aim at identifying the genes and developmental processes that depend upon these transcription factors to better understand how misregulation can be mitigated.

描述（申请人提供）：正常心脏的形成需要一系列基因的严格调控激活。这种调节在发育早期就开始了，因为细胞逐渐失去多能性并定居到形成肌肉、内皮、瓣膜和心脏结缔组织的谱系中。定义适当的谱系很重要，但同样重要的是，将这些不同的细胞类型建模到形成工作心脏的腔室、瓣膜、隔膜和传导系统中。 NK-2 蛋白家族的转录因子是心脏发育程序的调节因子之一。首先在果蝇中被鉴定为称为tinman的基因（因为无效突变导致果蝇无法形成背血管（果蝇的心脏）），现在我们将人类和其他脊索动物中的同源物称为Nkx2-5。即使 Nkx2-5 的一个拷贝发生突变，人类也会出现先天性心脏病。他们的问题包括分隔心室的畸形隔膜、心脏瓣膜缺陷和心脏收缩调节异常。最近，相关蛋白质 Nkx2-6 的突变被证明会导致心脏流出道出现问题，该区域将心脏泵出的血液连接回血管系统。 参与心脏形成的 NK-2 基因已在多种系统中得到了良好的研究，包括小鼠、鸡、苍蝇、鱼和青蛙非洲爪蟾。青蛙的监管分工属于该家族的三个成员：Nkx2-5、Nkx2-3 和 Nkx2-10（可能是人类 Nkx2-6 的同源物）。我们提出实验来追踪这些转录因子在早期心脏发育过程中的作用，定义每个转录因子赋予独特功能的蛋白质结构域，并确定每个转录因子的表达是如何调节的。这将使我们能够分离必须协调形成工作心脏的监管途径。 公共卫生相关性：人类先天性心脏缺陷影响着 1% 的新生儿，并对他们的余生带来持续的健康挑战。先天性心脏缺陷的遗​​传原因之一是转录因子 Nkx2-5 和 Nkx2-6 的突变，导致正确心脏形成所需的基因失调。这些研究旨在确定依赖于这些转录因子的基因和发育过程，以更好地了解如何减轻失调。