Murine strain sensitivity to cadmium teratogenesis

描述：（改编自申请人的摘要）：小鼠致畸，如 在许多生物医学科学中，有许多例子表明， 有据可查以前，在大多数情况下，这些基于基因型 差异报告没有一个系统的方法来确定 导致反应变化的因素。这一提议表明， 描述C57 BL/6 N和SWV之间差异的方法 应变镉诱导的轴后前肢缺趾（缺失的数字）。 C57 BL/6小鼠对该缺陷高度敏感，而SWV小鼠在 同样的剂量是完全耐药的建议使用多态 微卫星标记进行全基因组扫描或数量性状 基因座分析将鉴定代表特定基因的染色体基因座 导致了这种致畸性的菌株差异。随后的两次基因扫描 将进行致畸性结果与类似的应变反应。一 在不同的妊娠期使用相同的致畸剂（镉）， 不同的试剂（全反式视黄酸）诱导相同的 畸形后一种基因组扫描的目的是确定 在某种程度上，导致共同菌株差异的基因是相同的。 将进行实验，以确定镉是否进入胚胎， 胎盘在更大程度上处于敏感品系， 不同之处在于金属硫蛋白，一种镉结合蛋白。同类系小鼠 将被生产，然后繁殖，使多同源，以检查相互作用 菌株易感性的基因。两种不同的基因被认为是 镉致畸敏感性中重要因素cdm和6号染色体位点 标记为Cadfar的基因将被定位到基因组的特定位置， 克隆这些基因。一个包含9个基因的加性寡基因模型， 有人提出了诱发前肢缺陷的方法。

DESCRIPTION: (Adapted from the Applicant's Abstract): Mouse teratogenesis, like many biomedical sciences, has numerous instances where strain differences are well documented. Previously, in a majority of cases, these genotype-based differences were reported without a systemic approach for determining the factors causing the variability in response. This proposal suggests a genetic approach to characterizing the difference between the C57BL/6N and the SWV strains to cadmium-induced postaxial forelimb ectrodactyly (missing digits). The C57BL/6 mouse is highly sensitive to this defect while the SWV mouse at the same dose is totally resistant. It is suggested that the use of polymorphic micro satellite markers to perform a whole genome scan or quantitative trait locus analysis will identify chromosomal loci representative of specific genes responsible for this teratogenic strain difference. Two subsequent genome scans will be performed for teratogenic outcomes with a similar strain response. One with the same teratogen (cadmium) at a different gestational time and one in which a different agent (all-trans-retinoic acid) induces the same malformation. The goal of these latter genome scans is to determine to what extent the genes responsible for the common strain difference are the same. Experiments will be performed to determine if cadmium gets to the embryo or placenta to a greater extent in the sensitive strain, and whether the strains differ in terms of metallothionein, a cadmium-binding protein. Congenic mice will be produced and then bred to make polycongenics to examine the interaction of genes in strain susceptibility. Two different genes that are thought to be important in cadmium-sensitivity to teratogenesis, cdm and a chromosome 6 locus labeled Cadfar, will be mapped to specific locations in the genome as a prelude to cloning these genes. An additive oligogenic model involving nine genes for the induction of the forelimb defect has been proposed.