The Phex Pathway: Mechanisms Underlying a Meniere's Disease Subtype - Project Summary Meniere’s disease (MD), a chronic inner ear disorder characterized by debilitating symptoms of progressive hearing loss and episodic vertigo, arises from unclear etiology. Recent work from our institution identified a distinct subtype of MD – designated MDhp – representing a group of patients with hypoplasia of the endolymphatic sac and an altered trajectory of the bony vestibular aqueduct. Our unpublished data demonstrate a high co-incidence of MDhp and X-linked hypophosphatemia (XLH), a rare phosphate metabolism disorder caused by loss-of-function mutations in the PHEX gene that lead to high serum FGF23 levels and hereditary rickets. Preliminary data from our laboratory demonstrated that a Phex-deficient XLH mouse model recapitulates the auditory and vestibular loss, endolymphatic hydrops, and endolymphatic sac hypoplasia observed in the MDhp subtype in humans. The phenotypic and genotypic parallels between XLH mice and XLH humans with MDhp bring to the fore a new significance of the XLH mouse model, providing a robust animal model for a specific subtype of MD. The overarching hypothesis of this proposal is that mutations in the PHEX/Phex signaling pathway play a key role in the maldevelopment and dysfunction of the endolymphatic sac in both humans and a murine model, leading to the failure of inner ear homeostasis. The Candidate proposes a mentored training plan to leverage this human/mouse XLH model as a paradigm to investigate the causal mechanisms of the MDhp subtype, and lay the groundwork for broader studies into the pathophysiological mechanisms of MD. In Aim 1, the Candidate will establish the phenotypic and genotypic link between the MDhp subtype and XLH in humans to test the hypotheses that a portion of humans with XLH develop MDhp (Aim 1A) and that PHEX mutations are associated with the MDhp subtype with or without a clinical diagnosis of XLH (Aim 1B). In Aim 2, the Candidate will incorporate a Phex-deficient murine model of XLH to define the role of the Phex signaling pathway in the embryonic and early postnatal development of the endolymphatic sac and vestibular aqueduct to test the hypotheses that maldevelopment of the endolymphatic sac in Phex-deficient mice begins in utero (Aim 2A), Phex and FGF23 gene transcripts are expressed in the temporal bone in late embryonic time points (Aim 2B), and the administration of a monoclonal antibody to FGF23 to Phex-deficient mice in utero will “rescue” inner ear function (Aim 2C). The K08 award is a critical stepping-stone toward the Candidate’s goal of developing into an independent surgeon-scientist.
