The complex signaling network that comprises the innate immune system, metazoans' first line of defense against pathogens, has only begun to be elucidated. In mammals, the Toll-like receptor (TLR) family has been the subject of intense study; however, little is known about other innate immune signaling pathways and how they interact with the TLR cascade. The Caenorhabditis elegans - pathogen model system pioneered by the Ausubel lab will be used to undertake a molecular genetic analysis of innate immune signaling pathways. Specifically, fsh-1, a G-protein Coupled Receptor and homolog of the mammalian FSH receptor, plays an important role in worm innate immunity. Standard genetic techniques will be used to characterize the null phenotype of fsh-1. Expression of gfp-tagged fsh-1 from endogenous and heterologous promoters will elucidate its sub-cellular localization and tissue specificity. The molecules that transduce the fsh-1 signal and its interaction with known components of the innate immune response will be explored via reverse genetics and epistasis. Finally, a combination of molecular genetics and microarray analysis will determine the set of effectors regulated by fsh-1 and the signal(s) that trigger its activity. ? ? ?
