Host variability in innate inflammatory responses

描述（由申请人提供）：本提案的主要科学目标是确定遗传机制在控制细菌产物炎症反应的个体间变异性中所起的相对作用，并表征特定基因在决定这种变异性中的作用。拟议的研究将集中在体外对细菌脂多糖（LPS）的炎症反应上，这是一种中间表型，可能会导致个体发生败血症/感染性休克的部分风险。这些研究将开发一种方法，可以应用于其他可能导致败血症风险的中间表型，如对肽聚糖或细菌脂蛋白的反应。该奖项的主要培训目标是使首席研究员（PI）成为功能基因组学和遗传流行病学领域的独立研究者。通过教学课程和实践经验，PI将发展实现这一目标所需的技能。最终，PI希望开发一个独立的研究项目，研究宿主炎症反应的遗传决定因素，以确定败血症和ARDS临床结果的易感性。目的1将使用寡核苷酸阵列来确定正常个体对LPS表现出“高”和“低”反应（高和慢）细胞因子反应的基因表达差异。这些差异将用于创建一组“类描述符”基因，这些基因将前瞻性地识别lps高和lps低个体。目的2将使用经典的双胞胎研究来估计lps诱导的细胞因子反应的遗传和环境成分。然后，将使用异卵双胞胎进行定量兄弟对连锁分析，以评估来自LPS识别和信号通路内基因的单核苷酸多态性（SNP）单倍型与LPS诱导的细胞因子产生之间的连锁。目的3将测试假定的lps反应基因中的I型、II型或IV型snp与lps高表型和lps低表型中细胞因子产生之间的关系。鉴定与脂多糖异常高或低炎症反应的中间表型相关的snp将为未来败血症和ARDS的基因关联研究提供合理的候选基因。

DESCRIPTION (provided by applicant): The major scientific goal of this proposal is to determine the relative role that genetic mechanisms play in controlling inter-individual variability in inflammatory responses to bacterial products and to characterize the role of specific genes in determining this variability. The proposed studies will focus on 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/septic shock. These studies will develop an approach that can be applied to other intermediate phenotypes likely to contribute to risk for sepsis such as responses to peptidoglycan or bacterial lipoproteins. The major training goal of this award is for the Principal Investigator (PI) to develop as an independent investigator in the fields of functional genomics and genetic epidemiology. Through didactic courses and practical experience the PI will develop the skills needed to reach this goal. Ultimately, the PI wishes to develop an independent research program studying the genetic determinants of host inflammatory responses with the goal of determining susceptibility to the clinical outcomes of sepsis and ARDS. Aim 1 will use oligonucleotide arrays to determine differences in gene expression between normal individuals who show "hyper" and "hypo"-responsive (lpshigh and lpslow) cytokine responses to LPS ex vivo. These differences will be used to create a set of "class descriptor" genes that will prospectively identify lps high and lps low individuals. Aim 2 will use a classical twins study to estimate the heritable and environmental components to LPS-induced cytokine responses. Quantitative sib-pair linkage analysis will then be performed using the dizygotic twins to assess for linkage between single nueleotide polymorphism (SNP) haplotypes from genes within the LPS recognition and signaling pathway and LPS-induced cytokine production. Aim 3 will test for association between type I, II, or IV SNPs within putative LPS-response genes and cytokine production in the lps high and lps low phenotypes. Identification of SNPs that demonstrate linkage with the intermediate phenotypes of abnormally high or low inflammatory responses to LPS will provide rational candidates for future gene association studies in sepsis and ARDS.