GENETIC CONTRIBUTION TO THE STRESS RESPONSE

描述(改编自申请人的摘要)： 几天或几周后不同器官系统相继崩溃 严重创伤、败血症、胰腺炎和休克，称为多器官 功能障碍综合征(MODS)是导致死亡的最重要原因 以及住进外科重症监护病房的患者的发病率。 最近的研究表明，MODS是由压倒性的 炎症反应是宿主防御系统的一部分。一个重要的问题 临床观察是在患者身上观察到的异质性反应 在类似的压力之后。对这种观察结果的一个可能的解释是 对压力的反应受患者基因的影响 背景资料。因此，这项提案的中心重点是评价 基因多样性是否可能导致炎症反应 在压力过后。近交系小鼠品系将被用来检验这一假设。 这些信息将使我们更好地了解 炎症过程和调节血管内皮生长因子的基因的识别 炎症反应。这是一种新的方法来解决这个问题 使用传统方法一直难以找到解决方案。具体的 该项目的目标是：1)比较两种疾病的炎症反应 C57BL6/J和A/J小鼠。需要检验的假设是， 基因不同的小鼠品系C57BL6/J(B6)和A/J有 他们的炎症反应有显著差异。一种比较 这两种小鼠之间的炎症反应将是 在两个不同但相关的压力后执行：管理 大肠杆菌内毒素与盲肠结扎穿孔所致腹膜炎 (中电)。这项研究也与定量研究的发展有关 重组近交系小鼠品系筛选方法的研究 (特定目标2)，以及确定可能的候选基因 位置克隆努力(具体目标3)。2)定位负责的基因座 针对不同菌株在炎症反应中的差异。这个 调节B6炎症反应的表型(敏感)和 A/J(耐药)小鼠将在注射内毒素后表现出特征 或跟随中电。要使用的分析方法是：渗透 肝、肺中白细胞及血浆细胞因子水平的测定 (肿瘤坏死因子和白介素B)。管理这些响应的区域将使用RI进行映射 菌株(AxB和BXA)。3)候选基因的识别 炎症反应的差异。这些基因座的位置 对具体描述的表型贡献最大的 目标2将通过回交和交叉策略进行改进(高 分辨率作图)，并进行位置克隆工作。这个 这一分析结果将为我们提供候选基因 导致炎症反应的异质性。

DESCRIPTION (Adapted from the applicant's abstract): The sequential collapse of different organ systems days or weeks after severe trauma, sepsis, pancreatitis, and shock, termed multiple organ dysfunction syndrome (MODS), is the most important cause of mortality and morbidity of patients admitted to the surgical intensive care unit. Recent studies have suggested that MODS is caused by an overwhelming inflammatory response as part of the host defense system. One important clinical observation is the heterogeneous response observed in patients after similar stresses. A possible explanation for this observation is that the response to stress is influenced by the patient's genetic background. Thus, the central focus of this proposal is to evaluate whether genetic diversity may contribute to the inflammatory response after stress. Inbred mouse strains will be used to test this hypothesis. This information will provide us with a better understanding of the inflammatory process and the indentification of genes that modulate the inflammatory response. This is a novel approach to a problem whose solution has been elusive using conventional methodologies. The specific aims of the project are: 1) To compare the inflammatory response between C57Bl6/J and A/J mice. The hypothesis to be tested is that the genetically distinct mouse strains, C57Bl6/J (B6) and A/J have significant differences in their inflammatory response. A comparison of the inflammatory response between these two mouse strains will be performed after two different, but related, stresses: administration of E. coli LPS, and peritonitis induced by cecal ligation and puncture (CLP). This study is also pertinent to the development of quantitative assays for the screening of recombinant inbred (RI) mouse strains (Specific Aim 2), and the identification of possible candidate genes for a positional cloning effort (Specific Aim 3). 2) To map loci responsible for strain-specific differences in the inflammatory response. The phenotypes modulating the inflammatory response of B6 (sensitive) and A/J (resistant) mice will be characterized after administration of LPS or following CLP. The assays to be used are: the infiltration of leukocytes in liver and lung, and assessment of plasma cytokine levels (TNFa and IL-B). Loci governing these responses will be mapped using RI strains (AxB and BxA). 3) Identification of candidate genes contributing to differences in the inflammatory response. The positions of those loci with the strongest contribution to the phenotypes described in Specific Aim 2 will be refined with backcross and intercross strategies (high resolution mapping) and subjected to a positional cloning effort. The results from this analysis will provide us with candidate genes that contribute to the heterogeneity of the inflammatory response.