VITAMIN A SIGNALING AND CARDIAC MORPHOGENIC DEFECTS

维生素 A 信号传导和心脏形态缺陷

基本信息

批准号：
2234544
负责人：
KENNETH R CHIEN
金额：
$ 35.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 1999-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2234544
关键词：
VITAMIN SIGNALING CARDIAC MORPHOGENIC DEFECTS

VITAMIN SIGNALING CARDIAC MORPHOGENIC DEFECTS

项目摘要

DESCRIPTION (adapted from the applicant's abstract) The central objective of the current application will be to couple molecular and genetic-based approaches to the RXRa mouse model to determine whether the relative gene dosage level of RXRa can be an important determinant of the onset of specific cardiovascular malformations, to determine whether differences in genetic background can suppress the onset of specific cardiovascular malformations, to determine if breeding into other defined transgenic or gene-targeted backgrounds can promote or suppress the onset of these malformations, to identify the target genes that are downstream from RXRa and which are affected in these specific cardiovascular malformations, and to establish a transgenic rescue system capable of evaluation the role of specific downstream target genes in the onset of specific cardiovascular malformations using mouse genetic approaches. Accordingly, the Specific Aims are: 1) To determine if there is a gene dosage effect for the onset of specific cardiovascular malformations in the RXRa deficient mice; 2) To determine if genetic background and other modifying genes can promote or suppress the onset of specific cardiovascular malformations in the RXRa mice; 3) To identify a subset of the downstream target cardiac genes that are aberrantly expressed (mis, non, or over-expression) in the RXRa deficient mice and which closely correlate with the onset of specific cardiovascular malformation; and 4) To establish a transgenic approach for rescue of the cardiovascular defects in RXRa gene-targeted mice designed to ultimately allow an examination of the rescue capabilities of the downstream target genes, identified in Specific Aim III. Through the systematic analysis of the role for a specific member of the retinoid receptor gene family (RXRa), these studies should provide a molecular framework for the understanding how vitamin A deficiency can produce specific congenital heart malformations. By crossing into other genetic backgrounds and other transgenic/gene-targeted mouse lines, these studies should lead to the generation of strains of mice that spontaneously display defined cardiovascular malformations which should be valuable to explore the interaction of vitamin A/retinoid-dependent pathways with other nutritional deficiencies. In the event that downstream target genes are identified which are influenced by specific nutrients, (e.g., extracellular matrix genes that are vitamin C dependent, transcriptional factors that are sensitive to relative levels of zinc, etc.), these would provide insights as to which potential nutritional deficiencies might augment the onset of congenital heart malformations I the in vivo context. Finally, these studies should also lead to a system that employs genetic rescue to exact cause-effect relationships between a specific downstream target gene and specific subsets of cardiovascular malformations.

描述（根据申请人的摘要改编）中央当前应用的目的是夫妇分子和基于遗传的RXRA小鼠模型的方法，以确定是否是否 RXRA的相对基因剂量水平可能是重要的决定因素特定心血管畸形的发作，以确定是否遗传背景的差异可以抑制特定的发作心血管畸形，以确定是否繁殖到其他定义转基因或以基因为目标的背景可以促进或抑制发作这些畸形，以识别下游的靶基因来自RXRA，在这些特定心血管中受到影响畸形，并建立一个能够的转基因救援系统评估特定下游靶基因在发作中的作用使用小鼠遗传方法的特定心血管畸形。因此，具体目的是：1）确定是否存在基因特定心血管畸形发作的剂量效应 RXRA缺乏小鼠； 2）确定遗传背景和其他修改基因可以促进或抑制特定的发作 RXRA小鼠的心血管畸形； 3）识别子集异常表达的下游靶心基因（MIS，非表达或过表达）在RXRA缺乏小鼠中，哪些与特定心血管畸形的发作密切相关； 4）建立一种转基因方法来营救 RXRA基因靶向小鼠的心血管缺陷旨在最终允许检查下游目标的救援能力基因，在特定目标III中鉴定。通过对特定成员角色的系统分析视视视视视网想受体基因家族（RXRA），这些研究应提供分子框架，用于了解维生素A缺乏症如何如何产生特定的先天性心脏畸形。通过越过其他遗传背景和其他转基因/基因靶向小鼠系，这些研究应导致小鼠菌株产生自发显示定义的心血管畸形，应探索维生素A/类维生素依赖性的相互作用很有价值具有其他营养缺陷的途径。如果鉴定出受特定影响的下游靶基因。营养（例如，维生素C的细胞外基质基因对相对水平敏感的依赖性转录因子锌等），这些将提供有关哪些潜力的见解营养缺乏可能会增加先天性心脏的发作畸形i体内上下文。最后，这些研究也应该导致采用遗传救助的系统特定下游靶基因与特定的关系之间的关系心血管畸形的子集。