Identification of inflammatory processes modulator genes using the combined analysis of genomic fine mapping and global gene expression

• Grant number: 09/15822-0
• Support Opportunities: Regular Research Grants
• Duration: March 01, 2010 - February 29, 2012
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• Principal Investigator: Marcelo de Franco
• Grantee: Marcelo de Franco
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

The development of appropriate experimental models for studying the genetics of complex traits, such as antibody production and acute inflammatory reaction, has been the central object of our research line. These models result from the accumulation of allelic determinants of extreme phenotypes in lines of mice, through bidirectional genetic selection. The mice are interesting for identification of genes regulating these phenotypes and gene interaction studies of the interline differences observed for resistance or susceptibility to experimentally induced diseases. The main outcome of our research was the detection of several loci regulating the intensity of acute inflammation by microsatellite polymorphism analysis. Several candidate genes were identified within these loci, which also affect the determination of sensitivity to experimental diseases and tissue regeneration. Slc11a1 (formerly Nramp1) is one of these genes, which is involved in infection susceptibility and macrophage and neutrophil activity. This gene interacts with the regulatory acute inflammation loci, controlling the influx of neutrophils, the ability to regenerate tissue and the determination of high or low sensitivity to salmonella infection, its LPS, and to pristane induced arthritis. In another study, we demonstrate the involvement of the chromosome 6 distal region regulating the intensity of acute inflammatory reaction and susceptibility to lung cancer, which the main candidate is the Kras gene. Regarding to colon carcinogenesis, it was demonstrated that the animals selected for maximum acute inflammatory reaction (AIRmax) showed high susceptibility, although they are resistant skin and lung tumors. These studies have shown the involvement of immune and inflammatory cytokines in the various experimental disease protocols stimulated by acute or chronic inflammatory stimuli. Thus, to continue these studies we intend to: perform a fine mapping of quantitative trait loci (QTL) regulating the intensity of the acute and chronic inflammatory reactions using single nucleotide polymorphism (SNP) analysis in order to reduce the confidence intervals; address the global gene expression differences in the various protocols and correlate them with the QTL detected; and investigate the interaction of the main candidate genes in determining the phenotypes under investigation. (AU)