Characterization and treatment of an accelerated aging model of the olfactory epithelium - Project Summary Olfactory sensory neurons (OSNs) facilitate our sense of smell but constantly need to be replaced, likely because they are in direct contact with the external environment. The olfactory epithelium (OE) houses OSNs, and maintains our ability to smell throughout adulthood through nearly life-long neurogenesis. This remarkable ability for adult neurogenesis is not limitless, however. With increasing lifespan and a hostile external environment, a near majority of people develop hyposmia or anosmia by the age of 80. This is correlated with reduced quality of life, a slew of mental disorders, and malnutrition. Pathologic examination of aged human patient tissue suggests that olfactory neurogenic stem cells exhaust with age, and previously neuronal olfactory epithelium gradually becomes a-neuronal potentially even becoming respiratory epithelium. Unfortunately, no facile preclinical model that closely mimics this human OE pathology exists, hampering research and therapeutic development. Previous models were slow and poorly penetrant. Here, we describe a new model using an engineered nitroreductase enzyme (OMP-NTR2.0) that is highly effective at accelerating OSN turnover, can strikingly mimic aged human olfactory epithelium in as little as 12 weeks time, and could be used as the first platform for testing therapeutic approaches. In this grant, we propose to (Aim 1) extensively characterize this new model of accelerated aging in the OE, stage and compare it to human biopsy and donor tissue, (Aim 2) test the hypothesis that respiratory metaplasia results from conversion of exhausted olfactory epithelium as well as invasion from the surrounding respiratory epithelium, and finally, (Aim 3) test targeted therapies developed on our knowledge of olfactory epithelial stem cell dynamics. The objective of this proposal is to establish the OMP-NTR2.0 model as the viable preclinical model of age-associated olfactory dysfunction and use it to test first-generation therapeutic approaches. Our approach is innovative because it leverages a novel mouse model that we generated de novo that incorporates an engineered enzyme, which effectively accelerates aging of the olfactory epithelium and creates a platform for drug testing. Our long-term goal of our research is to develop prophylactic or curative treatments for age-associated anosmia.
