Estrogen Signaling in Urinary Tract Infection Related Delirium - ABSTRACT Delirium is a common complication of systemic illness that affects tens of millions annually with associated health care costs up to $152 billion/year in the United States alone. Delirium is associated with increased morbidity and mortality, prolonged hospitalization, and an accelerated declining trajectory of Alzheimer’s disease and related dementias (ADRD). Postmenopausal women, many with ADRD, are at disproportionately increased risk for developing delirium with UTI. In this proposal, we build on our previously published work involving the potential role for supplementing 17β-estradiol (E2), a hormone level that is reduced in the postmenopausal state, to ameliorate delirium. In this project we propose to determine the neuroprotective molecular mechanisms of E2 by utilizing estrogen receptor knockout strains to isolate the beneficial effects of E2 in mitigating UTI-induced delirium. We will also test an existing drug, bazedoxifene, that targets both the E2 signaling and IL-6 trans-signaling pathways, as a novel pharmacological treatment to reduce delirium. Finally, we propose to test the efficacy of endogenously enhancing E2 signaling through exercise to ameliorate UTI-induced delirium. Completion of these proposed studies will define neuroprotective mechanisms of E2 during UTI-induced delirium, provide support for bazedoxifene as a potential novel treatment that targets distinct components of delirium pathogenesis, and examine exercise as an environmental modifier of E2 signaling to protect against UTI-induced delirium in postmenopausal women.
