Host Determinants of the inflammatory response

这项建议的主要科学目标是确定控制细菌产物炎症反应中个体间可变性的分子机制，表征特定基因在确定这种可变性中的作用，并确定这些基因内的核苷酸可变性是否解释了临床综合征(如脓毒症和ALI/ARDS)中出现的部分可变性。这一建议背后的主要假设是，影响对细菌产物的体外炎症反应的基因变异将影响脓毒症和ALI/ARDS中严重炎症的临床结果。拟议的研究将使用对细菌脂多糖(LPS)的体外炎症反应作为研究这种变异性的探针。细菌脂多糖是一种中间表型，可能导致个人发生脓毒症和ALI/ARDS的风险的一部分。AIM 1的研究将使用寡核苷酸阵列和蛋白质组水平分析来确定基因和蛋白质表达的差异 在体外对脂多糖表现出“高”和“低”反应(LPs[高]和[Lps[低])细胞因子反应的正常人之间。在目标2中，我们提出了一项经典的双胞胎研究，以估计内毒素诱导的细胞因子反应的遗传和环境成分。在目标3中，我们将测试假定的内毒素反应基因中的SNP单倍型与体外细胞因子反应之间的关联。在目标4中，将在脓毒症和ALI/ARDS的临床人群中测试被确定为与目标3中的炎症反应相关的内毒素反应基因中的SNP单倍型与临床结果的相关性。人们希望，识别能够增加(或降低)不良结局风险的SNP单倍型 在感染性休克和ARDS中，将能够前瞻性地确定哪些患者将从实验干预中受益。此外，通过这些研究开发的算法将适用于对可能导致脓毒症和ALI/ARDS发展风险的其他细菌产品的炎症反应。

The major scientific goals of this proposal are to determine the molecular mechanisms controlling inter-individual variability in inflammatory responses to bacterial products, to characterize the role of specific genes in determining this variability, and to determine whether nucleotide variability within these genes explains a portion of the variability seen in the clinical syndromes such as sepsis and ALI/ARDS. The primary hypothesis behind this proposal is that genetic variation that influences in vitro inflammatory responses to bacterial products will influence clinical outcomes in the severe inflammation seen in sepsis and ALI/ARDS. The proposed studies will employ inflammatory responses to bacterial lipopolysaccharide (LPS) ex vivo, an intermediate phenotype likely to contribute a portion of the risk of an individual to the development of sepsis and ALI/ARDS, as a probe to study this variability. Studies in Aim 1 will use oligonucleotide arrays and proteome-level analysis to determine differences in gene and protein expression between normal individuals who show "hyper" and "hypo"-responsive (lps[high] and lps[low]) cytokine responses to LPS ex vivo. In Aim 2, we propose a classical twins study to estimate the heritable and environmental components to LPS-induced cytokine responses. In Aim 3 we will test for association between SNP haplotypes within putative LPS-response genes and the ex vivo cytokine responses. In Aim 4, SNP haplotypes within LPS-response genes identified as being associated with the inflammatory response in Aim 3 will be tested in a clinical population of patients with sepsis and ALI/ARDS for association with clinical outcomes. It is hoped that identification of SNP haplotypes that confer increased (or decreased) risk for adverse outcomes in septic shock and ARDS will allow the prospective identification of patients who will benefit from experimental interventions. Furthermore, the algorithms developed through these studies will be applicable to inflammatory responses to other bacterial products that may contribute to the risk for development of sepsis and ALI/ARDS.