Project Summary
It is well-established that premenopausal females have blood pressure that is ~10mmHg lower
than that of males. We previously reported that an evolutionarily conserved olfactory receptor,
OLFR558, is expressed in the kidney; we have now uncovered that OLFR558 is required for sex
differences in blood pressure. OLFR558 localizes to renin-containing juxtaglomerular cells in the
kidney, and to vascular smooth muscle cells. KO females exhibit increased blood pressure (and
increased pulse wave velocity), whereas KO males exhibit decreased blood pressure (and
decreased renal expression of renin, and, decreased plasma renin activity). As a result, blood
pressure is similar in KO males and females. Our understanding of OLFR558’s role is currently
hindered by our poor understanding of OLFR558 ligands. The central Aim of this proposal is to
advance our understanding of OLFR558 ligands in order to better develop our understanding of
OLFR558 physiology. In Aim 1, we will work to better understand putative endogenous ligands
of OLFR558. To date, we have identified 18 ligands which activate OLFR558 in vitro; however,
it is unclear how many of these ligands circulate at levels that activate OLFR558 in vivo (Aim
1a). Of note, several of these ligands modulate additional pathways; thus, we will measure
blood pressure responses to each ligand in both OLFR558 WT and KO mice to define the
OLFR558-mediated response (Aim 1b). Several of the best ligands for OLFR558 are produced
by microbiota; in Aim 2 we will determine if the commensal microbiome influences OLFR558
signaling. Finally, in Aim 3, we will leverage our recent success in discovering novel synthetic
OLFR558 agonists with high potency and selectivity, as well as a novel OLFR558 antagonist.
These novel probes will be used as research tools to selectively manipulate OLFR558 activity in
vivo; at the same time, this Aim will explore the therapeutic potential of these novel ligands.