Host Determinants of the inflammatory response

该提案的主要科学目标是确定控制细菌产物炎症反应个体间变异性的分子机制，表征特定基因在确定这种变异性中的作用，并确定这些基因内的核苷酸变异性是否解释了败血症和ALI/ARDS等临床综合征中观察到的部分变异性。该提议背后的主要假设是，影响对细菌产物的体外炎症反应的遗传变异将影响脓毒症和ALI/ARDS中观察到的严重炎症的临床结果。拟议的研究将采用对细菌脂多糖（LPS）的离体炎症反应作为研究这种变异性的探针，LPS是一种中间表型，可能导致个体发生脓毒症和ALI/ARDS的部分风险。目标1中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 在离体对LPS显示“高”和“低”应答（LPS[高]和LPS[低]）细胞因子应答的正常个体之间。在目标2中，我们提出了一个经典的双胞胎研究，以估计遗传和环境因素对LPS诱导的细胞因子反应。在目标3中，我们将测试推定的LPS应答基因内的SNP单倍型与离体细胞因子应答之间的关联。在目标4中，将在脓毒症和ALI/ARDS患者的临床人群中测试目标3中鉴定为与炎症反应相关的LPS应答基因内的SNP单倍型与临床结局的相关性。人们希望，SNP单倍型的鉴定，赋予增加（或减少）的风险，为不良后果 在感染性休克和ARDS中的应用将允许前瞻性地识别将从实验性干预中受益的患者。此外，通过这些研究开发的算法将适用于对可能导致败血症和ALI/ARDS发展风险的其他细菌产物的炎症反应。

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.