FATTY ACID HOMEOSTASIS IN C. ELEGANS AND MAMMALS: PAQR-2/ADIPOR, HYPOXIA AND OTHER PATHWAYS

Fatty acids come in a variety of lengths and unsaturation and serve in energy storage, as structural components of membranes and as precursors of signaling molecules. Given their critical roles, surprisingly little is known about the mechanisms of fatty acid homeostasis.

Using C. elegans, we discovered the first sensor/regulator of membrane homeostasis in animals: it is composed of two proteins, PAQR-2 and IGLR-2, which are homologs of the mammalian ADIPOR1/2 proteins and of LRIG-type proteins, respectively.

More recently, we have completed a forward screen for mutations that compensate for a deficiency of polyunsaturated fatty acids (PUFAs) in C. elegans and begun characterizing evolutionarily conserved genes that are required for tolerance to saturated fatty acids (SFAs).The aims of the present proposal are three-fold:1) Define the ultrastructural and physiological consequences of PAQR-2/ADIPOR2 deficiency and develop gain-of-function alleles of these proteins.2) Characterize the suppressors of PUFA deficiency in C. elegans to understand how cells can compensate for a PUFA shortage.3) Leverage C. elegans genetics to elucidate the mechanisms of action of several genes previously identified as essential for SFA tolerance in human cells.Our research relies on C. elegans as a model for making fundamental advances that are then verified in mammalian models.