Host Variability in Innate Inflammatory Responses

PI: Mark Wurfel
Project Number: 1K23HL072923
Project Dates: 9/8/2003-8/31/2008

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.