Mouse QTL in Endotoxic Shock

描述(申请人提供)：本实验为设计实验 以确定参与调节炎症反应的基因。一个 炎症反应对维持体内平衡至关重要 来自生物体外的入侵。但是，当此响应不正确时 如果受到监管，它可能会对宿主有害。多器官功能障碍 综合征(MODS)，一种由于调节不当而导致的临床状况 炎症反应，是导致发病和死亡的最重要原因 在外科重症监护室。这种情况是一种复杂的特征，导致 是遗传、环境和随机因素共同作用的结果。确实有 目前还没有预测哪些患者可能是遗传性的 先入为主。定位影响这一结果的QTL是有问题的 远亲繁殖的自由放养物种。 关于生物化学、细胞和生物体的信息非常丰富。 内毒素诱导炎症反应的生物学。我们已经证明了 近交系小鼠之间的遗传差异导致或多或少的 炎症反应。观察到了几种表型的显著差异。 A/J和C57BL/6J(B6)小鼠之间。我们已经定位了影响两个性状的QTL 在这些品系的小鼠之间存在显著差异，内毒素诱导的渗透 肝脏中性粒细胞的数量，以及培养的脾B细胞对 LP。将使用几种映射策略来改进本地化 这些QTL。已经为最初的位置克隆工作选择了两个基因座， 并对具体策略进行了探讨。通过这种方法识别的基因将 用于启动对调节炎症的途径的分析 在分子、细胞和系统水平上的反应。其中特定于菌株的 确定了导致表型差异的变异， 对这些分子变化的理解将与统计学相关 关于遗传方式的预测(座位是显性的，隐性的， 添加剂、改性)。此信息将用于解释和进一步 开发检测QTL的方法。

DESCRIPTION (provided by applicant): The experiments proposed here are designed to identify genes involved in the regulation of the inflammatory response. An inflammatory response is essential to maintain homeostasis in the face of invasion from outside the organism. However, when this response is not properly regulated, it can be detrimental to the host. Multiple organ dysfunction syndrome (MODS), a clinical condition that results from an improperly regulated inflammatory response, is the most important cause of morbidity and mortality in surgical intensive care units. This condition is a complex trait, resulting from a combination of genetic, environmental and stochastic factors. There are currently no predictors as to which individual patients may be genetically predisposed. Mapping QTL contributing to this outcome is problematic in outbred, free-ranging species. A wealth of information exists about the biochemistry, cell, and organismal biology of endotoxin-induced inflammatory response. We have demonstrated that genetic variation between inbred strains of mice results in a greater or lesser inflammatory response. Robust differences in several phenotypes were observed between A/J and C57BL/6J (B6) mice. We have mapped QTL affecting two traits that vary significantly between these strains of mice, LPS-induced infiltration of PMN in the liver, and the mitogenic response of cultured splenic B cells to LPS. Several mapping strategies will be used to refine the localization of these QTL. Two loci have been chosen for initial positional cloning efforts, and specific strategies are discussed. Genes identified by this approach will be used to initiate analysis of the pathways regulating the inflammatory response at molecular, cellular and systemic levels. Where strain-specific variants are identified that account for differences in phenotype, understanding of these molecular changes will be related to statistical predictions about the mode of inheritance (loci which are dominant, recessive, additive, modifying). This information will be used to interpret and further develop methods for detecting QTL.