Cadmium Teratogenesis to murine strains proteomics

描述（由申请人提供） 多年来，生物学家一直在描述小鼠品系的差异，但没有确定潜在的原因。 本研究的目的是描述镉诱导的致畸作用中小鼠品系差异的原因。 更具体地说，已经表明C57 BL/6 N株对镉给药引起的前肢缺指（趾缺失）的诱导敏感，而SWV/Fnn株对镉给药引起的前肢缺指（趾缺失）的诱导具有抗性。 据推测，蛋白质组学的方法，系统地检查两个鼠株之间的蛋白质水平的差异，无论是内源性的，以及镉暴露后，将是有用的菌株差异的识别机制途径。 虽然这种方法将产生小鼠品系之间的有形差异，它建议，通过比较分析蛋白质组学结果与基因表达谱和数量性状基因座（QTL）分析，两种方法被独立地用来解决这个相同的问题，提高了确定菌株差异的原因的可能性。 QTL分析初步确定了9个与该显性寡基因性状连锁的染色体位点。 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，则这将显著增强两个结果。 假设通过全基因组连锁分析、基因表达谱分析和蛋白质组学分析来研究镉诱导的小鼠品系在该畸形中的差异，个体结果将协同产生更显著和更全面的答案，以回答品系差异对镉诱导的致畸作用的因果关系问题。 然而，由于这种相同的菌株差异（C57比SWV更敏感）存在于所有已被证明会导致这种特定畸形的致畸剂中，包括一些突出的致畸剂，如全反式维甲酸，乙酰唑胺，高热和乙醇，因此本研究的目标是确定致畸作用中基因-环境相互作用的一些基本方面。

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.