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：
8469049
负责人：
DANIEL L. WEEKS
金额：
$ 30.67万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469049
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.

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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lessons from the lily pad: Using Xenopus to understand heart disease.

睡莲叶的教训：利用非洲爪蟾了解心脏病。

DOI：
10.1016/j.ddmod.2009.02.006
发表时间：
2008
期刊：
Drug discovery today. Disease models
影响因子：
0
作者：
Bartlett,HeatherL;Weeks,DanielL
通讯作者：
Weeks,DanielL

Activation of a T-box-Otx2-Gsc gene network independent of TBP and TBP-related factors.

DOI：
10.1242/dev.127936
发表时间：
2016-04-15
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Gazdag E;Jacobi UG;van Kruijsbergen I;Weeks DL;Veenstra GJ
通讯作者：
Veenstra GJ

Using ΦC31 integrase to mediate insertion of DNA in Xenopus embryos.

使用 δC31 整合酶介导非洲爪蟾胚胎中 DNA 的插入。

DOI：
10.1007/978-1-61779-992-1_13
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Li,YouE;Allen,BryanG;Weeks,DanielL
通讯作者：
Weeks,DanielL

Amyloids assemble as part of recognizable structures during oogenesis in Xenopus.

DOI：
10.1242/bio.017384
发表时间：
2016-06-15
期刊：
Biology open
影响因子：
2.4
作者：
Hayes MH;Weeks DL
通讯作者：
Weeks DL

Echocardiographic assessment of cardiac morphology and function in Xenopus.

非洲爪蟾心脏形态和功能的超声心动图评估。

DOI：
发表时间：
2010
期刊：
Comparative medicine
影响因子：
0.8
作者：
Bartlett,HeatherL;Escalera2nd,RobertB;Patel,SonaliS;Wedemeyer,ElesaW;Volk,KennethA;Lohr,JamieL;Reinking,BenjaminE
通讯作者：
Reinking,BenjaminE