Molecular basis of neuronal diversity in olfaction and its functional implications

Abstract

Odorants are recognized by a large family of odorant receptors (ORs), expressed in the olfactory neurons. The human OR family is composed of ~ 400 genes. In this project we aim to analyze four molecular aspects concerning the olfactory system: (1) We will analyze how variable is the repertoire of ORs of individuals from diverse geographical and cultural backgrounds. (2) Olfactory dysfunctions are known to serve as early markers of neurodegenerative diseases. We will develop a method to select peptides from neurotropic pathogens that are able to penetrate the mouse brain via the olfactory route. We also plan to investigate whether there is a correlation between variants of ORs with neurodegenerative diseases. (3) Ric-8B is a protein that has an essential role for olfaction. We will interrogate the mechanisms of action of Ric-8B in these systems by: (a) determining its subcellular localization in olfactory neurons and in striatum cells, where Ric-8B is also expressed; (b) analysis of the olfactory epithelium of Ric-8B cKO mice; (c) analysis of conditional deletion of Ric-8B in the striatum; (d) analysis of human Ric-8B gene variants in the population. (4) A subpopulation of olfactory neurons, with as yet unknown functions in olfaction, expresses CD36, a multifunctional membrane glycoprotein involved in lipid transport and signaling. We will investigate the gene expression mechanisms that differentiate these neurons from the canonical ones. (AU)