GENETIC CONTRIBUTION TO THE STRESS RESPONSE

描述（改编自申请人摘要）： 几天或几周后不同器官系统的相继衰竭 严重创伤、败血症、胰腺炎和休克，称为多器官 多器官功能障碍综合征（MODS）是最重要的死亡原因 和入住外科重症监护室的患者的发病率。 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 临床观察是在患者中观察到的异质性反应 类似的压力。对这一观察结果的一个可能解释是 对压力的反应受到病人基因的影响 背景因此，本提案的核心重点是评估 遗传多样性是否会导致炎症反应 压力之后。将使用近交系小鼠品系来检验该假设。 这些信息将使我们更好地了解 炎症过程和识别基因调节 炎症反应。这是一个新的方法来解决一个问题， 使用常规方法解决方案是难以实现的。具体 该项目的目的是：1）比较 C57 B16/J和A/J小鼠。要检验的假设是， 遗传上不同的小鼠品系，C57 B16/J（B6）和A/J具有 在炎症反应方面有显著差异。的比较 这两种小鼠品系之间的炎症反应将是 在两种不同但相关的应激后进行： E.大肠杆菌LPS和盲肠结扎穿孔腹膜炎 （CLP）。这项研究也与定量的发展有关。 用于筛选重组近交（RI）小鼠品系的测定 （具体目标2），并确定可能的候选基因， 定位克隆的努力（具体目标3）。2)为了定位 在炎症反应中的菌株特异性差异。的 调节B6的炎症反应的表型（敏感）， A/J（抗性）小鼠将在给予LPS后进行表征 或遵循CLP。待使用的测定是： 肝和肺中的白细胞以及血浆细胞因子水平的评估 (TNFa和IL-B）。控制这些响应的位置将使用RI进行映射 AxB和BxA。3)候选基因的鉴定 炎症反应的差异。这些位点的位置 对表型的贡献最大， 目标2将与回交和互交策略（高 分辨率作图）并进行定位克隆。的 该分析的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.