Nkx2-5 and congenital heart defects in Xenopus

Nkx2-5 与爪蟾先天性心脏缺陷

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：正常心脏的形成需要一系列基因的严格调节。由于细胞逐渐失去多能性并定居于导致肌肉，内皮，瓣膜和心脏结缔组织的谱系中，因此这种调节始于发育。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的建模到形成工作心脏的腔室，瓣膜，隔膜和传导系统中。心脏发育计划的调节剂中有NK-2家族的转录因子。首先在果蝇中被鉴定为称为Tinman的基因（因为无效突变产生了未能形成背部血管（苍蝇的心脏）的果蝇），我们现在将人类和其他弦的同源物称为NKX2-5。即使在NKX2-5副本之一中具有突变的人类也会出现先天性心脏缺陷。他们的问题包括畸形的隔膜分离心脏的腔室，心脏瓣膜缺陷和心脏收缩异常调节。最近，相关蛋白质NKX2-6中的突变被证明会引起心脏流出道的问题，该区域将心脏泵回血液泵回血管系统的区域。已经研究了涉及心脏形成的NK-2基因在各种系统中具有良好的优势，包括小鼠，鸡，蝇，鱼和青蛙Xenopus laevis。青蛙的劳动划分属于该家族的三名成员NKX2-5，NKX2-3和NKX2-10（人类NKX2-6的可能同源物）。我们提出的实验以跟踪早期心脏发育过程中每个转录因子的作用，定义每个赋予独特功能的蛋白质结构域，并确定每个调节的表达方式。这将使我们能够分开必须协调形成工作心脏的监管途径。公共卫生相关性：人类的先天性心脏缺陷会影响所有新生儿的1％，并对他们的余生提出了持续的健康挑战。先天性心脏缺陷的遗传原因之一是转录因子NKX2-5中的突变，而NKX2-6导致了正确的心脏形成所需的基因的正调。这些研究旨在识别依赖这些转录因子的基因和发育过程，以更好地了解如何减轻错误调节。