Cadmium Teratogenesis to murine strains proteomics

镉对小鼠品系蛋白质组学的致畸作用

• 批准号: 6657400
• 负责人: MICHAEL David COLLINS
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-10 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657400
• 关键词: SDS polyacrylamide gel electrophoresis; animal tissue; cadmium; congenital disorders; embryo /fetus cell /tissue; environmental exposure; gene environment interaction; gene expression; gene expression profiling; high performance liquid chromatography; laboratory mouse; linkage mapping; mass spectrometry; messenger RNA; posttranslational modifications; proteomics; quantitative trait loci; technology /technique development; teratogens; toxicology

DESCRIPTION (provided by applicant) For years, biologists have described murine strain differences without determining the underlying causation. The purpose of this research effort is to delineate the reasons for a murine strain difference in cadmium-induced teratogenesis. More specifically, it has been shown that the C57BL/6N strain is susceptible and the SWV/Fnn strain is resistant to the induction of forelimb ectrodactyly (absence of digits) by cadmium administration. It is hypothesized that a proteomics approach to systematically examine differences in protein levels between the two murine strains, both endogenously as well as following cadmium exposure, will be useful for identifying mechanistic pathways for the strain difference. Although this approach will yield tangible differences between the murine strains, it is suggested that by comparatively analyzing the proteomic results together with gene expression profiling and quantitative trait loci (QTL) analysis, two approaches that are being utilized independently to address this same question, the possibility of determining the cause of the strain difference is enhanced. The QTL analysis has preliminarily determined nine chromosomal loci that are linked to the apparently oligogenic trait. If any of the differentially expressed transcripts or proteins can be determined to be from genes that are in the chromosomal regions identified in the QTL analysis, this would significantly enhance both results. It is hypothesized that by examining the cadmium-induced murine strain difference in this malformation via whole genome linkage analysis, gene expression profiling and proteomic analysis, that the individual results will synergize to yield a more significant and comprehensive answer to the question of the causation of the strain difference to cadmium-induced teratogenesis. However, since this same strain difference (C57 more sensitive than SWV) exists for all of the teratogenic agents that have been shown to cause this specific malformation, including some prominent teratogens such as all-trans-retinoic acid, acetazolamide, hyperthermia, and ethanol, it is a goal of this research to determine some fundamental aspects of gene-environment interactions in teratogenesis.

描述（由申请人提供） 多年来，生物学家描述了小鼠品系的差异，但没有确定根本原因。 本研究的目的是阐明镉诱导畸胎作用中小鼠品系差异的原因。 更具体地，已表明C57BL/6N品系对镉施用引起的前肢外指畸形（缺乏手指）敏感，而SWV/Fnn品系对诱导的前肢外指畸形（缺乏手指）有抵抗力。 据推测，系统地检查两种小鼠品系之间的蛋白质水平差异（内源性以及镉暴露后）的蛋白质组学方法将有助于识别品系差异的机制途径。 尽管这种方法会在小鼠品系之间产生明显的差异，但建议通过比较分析蛋白质组结果以及基因表达谱和数量性状位点（QTL）分析，这两种方法独立用于解决同一问题，提高了确定应变差异原因的可能性。 QTL分析初步确定了与明显寡基因性状相关的9个染色体位点。 如果可以确定任何差异表达的转录物或蛋白质来自 QTL 分析中鉴定的染色体区域中的基因，这将显着增强这两个结果。 据推测，通过全基因组连锁分析、基因表达谱和蛋白质组分析来检查镉诱导的小鼠品系在这种畸形中的差异，各个结果将协同作用，从而对因果关系问题产生更重要和更全面的答案。镉诱导致畸的菌株差异。 然而，由于所有致畸剂都存在这种相同的菌株差异（C57 比 SWV 更敏感），这些致畸剂已被证明会导致这种特定的畸形，包括一些显着的致畸剂，例如全反式视黄酸、乙酰唑胺、热疗和乙醇，本研究的目标是确定致畸过程中基因与环境相互作用的一些基本方面。