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。这项研究工作的目的是描述在镉诱导的致畸方面小鼠品系差异的原因。更具体地说，C57BL/6N品系是敏感的，而SWV/FNN品系对镉诱导的前肢指缺失(指缺失)具有抗性。据推测，用蛋白质组学的方法系统地检测两个品系之间蛋白质水平的差异，无论是在内源性还是在镉暴露之后，都将有助于识别品系差异的机制途径。尽管这种方法将在小鼠品系之间产生明显的差异，但有人建议，通过比较分析蛋白质组结果以及基因表达谱和数量性状基因座(QTL)分析，这两种单独用于解决同一问题的方法，增加了确定品系差异原因的可能性。QTL分析初步确定了与这一明显的少基因性状相关的9个染色体座位。如果能够确定任何差异表达的转录本或蛋白质来自QTL分析中确定的染色体区域的基因，这将显著增强这两个结果。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检测镉致畸小鼠品系的差异，个体结果将协同作用，对品系差异导致镉致畸的原因这一问题做出更有意义和更全面的回答。然而，由于相同的菌株差异(C57比SWV更敏感)存在于所有已被证明导致这种特殊畸形的致畸剂中，包括一些突出的致畸因素，如全反式维甲酸、乙酰唑胺、高温和乙醇，因此本研究的目标是确定致畸中基因-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.