Molecular basis of neuronal diversity in olfaction and its functional implications

• Grant number: 22/12481-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: November 01, 2023
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Bettina Malnic
• Grantee: Bettina Malnic
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Isaias Glezer ; Ricardo Jose Giordano ; Tábita Hünemeier
• Associated research grant(s): 24/01998-0 - Lipid dynamics of olfactory neuron cilia: Implications for olfactory receptor functionality, AP.R
• Associated scholarship(s): 26/01545-0 - Human OR and Ric-8B gene variants and diseases, BP.DR; 25/03657-8 - Olfactory neurons: different types and their functions, BP.PD; 24/02568-9 - Diversity of odorant receptors and Ric-8B and their implications for olfaction, BP.PD; 24/02554-8 - Using transgenic and wild mice to analyse olfactory mechanisms, BP.TT

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)