Lipid Homeostasis in C. elegans

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DESCRIPTION (provided by applicant): Obesity and obesity-related diseases account for -300,000 deaths each year. Identification of molecules involved in energy metabolism and an understanding of their function is critical to combat this devastating disease. The discovery that factors controlling energy metabolism are conserved between mammals and C. elegans has provided a new and powerful strategy to delineate the molecular pathways that lead to obesity. Our focus is the transcriptional component of metabolic control in the digestive tract. We have discovered that the PHA-4/FoxA transcription factor is a key regulator of lipid homeostasis in C. elegans and is controlled by components of the TOR and insulin signalling pathways. Recent findings have suggested that that FoxA factors also function in mammals to control lipid metabolism. Therefore, the pathways we discover in C. eiegans are likely to be relevant to human health and disease. We propose to extend our initial observations in three ways. i) First we will investigate the regulatory circuitry that modulates PHA-4 activity in the digestive tract. We will use genetic and molecular approaches to place pha-4 in the signalling pathways, and we will initiate structure/function studies to elucidate the nature of the regulation. ii) Second we will use molecular and bioinformatic approaches to identify and characterize direct PHA-4 target genes. This analysis will distinguish between different models of PHA-4 function. iii) Third, we will use genetic interactions with pha-4 as the basis of a screen for new genes in the lipid storage pathway. Our preliminary data suggest that our strategy will discover genes missed in previous screens. These three approaches will elucidate the transcriptional network for fat metabolism within the C. elegans digestive tract