Determining the position and role of MafB and Krox20 in the cardiac neural crest cell gene regulatory program

确定 MafB 和 Krox20 在心脏神经嵴细胞基因调控程序中的位置和作用

基本信息

批准号：
9262072
负责人：
Michael Louis Piacentino
金额：
$ 5.67万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262072
关键词：
Ablation Address Behavior Binding Sites Biological Neural Networks Biology Blood Circulation Cardiac Cardiac development Cardiovascular system Cells Cephalic Chick Embryo Congenital Abnormality Congenital Heart Defects Defect Development EGR2 gene Ectopic Expression Embryo Enhancers Environment Etiology Failure Foundations Future Gene Expression Genes Genetic Transcription Goals Heart Abnormalities Heart Valves Histology Human Development In Situ Hybridization Knowledge Learning Live Birth Lung Molecular Morphology Mutate Neural Crest Neural Crest Cell Operative Surgical Procedures Peripheral Nervous System Plant Roots Play Population Positioning Attribute Preparation Principal Investigator Process Property Regulator Genes Regulatory Element Reporter Research Personnel Research Proposals Role Skeleton System Techniques Testing Therapeutic Time Tissues To specify Training Validation Ventricular septum base cardiogenesis career cell type craniofacial experience experimental study gene product interest loss of function migration multipotent cell nano-string network models neurodevelopment novel novel therapeutics post-doctoral training prevent programs public health relevance repaired skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): The cardiac neural crest is a unique population of cells that undergo extensive migration through the embryo and contribute to many aspects of cardiac development, including the formation of the interventricular septum, the partitioning of the cardiac outflow tract, and the development of the heart valves. Defects in cardiac neural crest are at the root of many congenital heart defects found in live births, and these issues often require surgical repair. Despite this clear importance in human development, our understanding of cardiac neural crest biology remains incomplete. Here we propose to determine the role of two transcription factors, MafB and Krox20, in the development of the cardiac neural crest. Interestingly, these two factors are expressed in the migrating cardiac neural crest, and not in other migrating neural crest populations, suggesting that they play specific roles in cardiac neural crest development. As transcription factors, MafB and Krox20 function to regulate expression of additional genes, and thereby they can have broad impacts on the behavior of the cardiac neural crest cells. By eliminating MafB and Krox20 function in the chick cardiac neural crest we will identify any resulting defects. We hypothesize that loss of MafB or Krox20 will result in cardiac defects that closely resemble many congenital heart defects, and thereby demonstrate the importance of these gene products for normal cardiac neural crest development. To achieve these goals, we will examine not only cardiac morphology, but also the migratory path taken by the cardiac neural crest cells, as well as the expression of target downstream genes through candidate-based and systems-level experiments. We will also identify important transcriptional inputs into MafB and Krox20 expression. Following these experiments, we will assemble a gene regulatory network model that describes the cascade of gene expression upstream and downstream of MafB and Krox20 in the cardiac neural crest, and provides the necessary framework to determine what makes the cardiac neural crest unique from other neural crest linages. This knowledge will inform future studies in which other neural crest cells will be "reprogrammed" to compensate for loss of cardiac neural crest, and thereby rescue cardiac neural crest-related congenital heart defects.

描述（由申请人提供）：心脏神经嵴是一种独特的细胞群，它们在胚胎中进行广泛的迁移，并有助于心脏发育的许多方面，包括室间隔的形成、心脏流出道的分隔和心脏瓣膜的发育缺陷是活产中发现的许多先天性心脏缺陷的根源，而这些问题经常发生。尽管在人类发育中具有明显的重要性，但我们对心脏神经嵴生物学的理解仍然不完整，在这里我们建议确定两种转录因子 MafB 和 Krox20 在心脏神经嵴发育中的作用。 MafB 和 Krox20 在迁移性心脏神经嵴群体中表达，而不是在其他迁移性神经嵴群体中表达，这表明它们在心脏神经嵴发育中发挥特定作用。基因，因此它们可以对心脏神经嵴细胞的行为产生广泛的影响，通过消除雏鸡心脏神经嵴中的 MafB 和 Krox20 功能，我们将识别任何由此产生的缺陷。与许多先天性心脏缺陷非常相似的缺陷，从而证明这些基因产物对正常心脏神经嵴发育的重要性。为了实现这些目标，我们不仅要检查心脏形态，还要检查心脏神经的迁移路径。嵴细胞，以及通过基于候选和系统级实验的目标下游基因的表达，我们还将确定 MafB 和 Krox20 表达的重要转录输入。心脏神经嵴中 MafB 和 Krox20 上游和下游的基因表达级联，并提供必要的框架来确定心脏神经嵴与其他神经嵴谱系的独特之处。这些知识将为未来的研究提供信息。其他神经嵴细胞将被“重新编程”以补偿心脏神经嵴的损失，从而挽救与心脏神经嵴相关的先天性心脏缺陷。