Advanced search
Start date
Betweenand

Integration of quantitative lipidomic and oxy-lipidomic analysis to trace dysregulated pro-inflammatory pathways involved in infectious and neurodegenerative diseases

Grant number: 20/08175-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2020
Effective date (End): August 31, 2022
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Sayuri Miyamoto
Grantee:Adriano de Britto Chaves Filho
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

Oxidative stress and inflammation are closely linked to infectious and neurodegenerative processes. Polyunsaturated fatty acids (PUFAs), such as arachidonic (ARA, n-6) and docosahexaenoic (DHA, n-3) acids play a pivotal role in this event as precursors of pro-inflammatory or pro-resolving oxidized products. During an infectious or neurodegenerative process, a set of signaling oxylipids are involved in different stages of inflammation and cell death pathways (apoptosis, efferocytosis). Thus, tracking the lipids in a time-dependent and isotopically labeled manner could help to discriminate the balance between deleterious/pro-resolving mediators and understand how they participate and regulate cellular events associated to cell death and/or pro-resolving effects. Among different lipid species, we have been focused on understanding the formation and biological effects of oxygenated PUFA species (either free or esterified to glycerolipids or glycerophospholipids) and steroids in neurodegenerative diseases, particularly in ALS. However, analysis of the oxi-lipidome is challenging due to the huge diversity and small amounts of oxygenated lipid species produced in vivo, thus one of the first aims of this project is to develop a robust comprehensive and sensitive method to monitor/quantify these species. The second and third aims of this project use cellular models and isotopically labeled PUFA precursors to track the role of n-6 and n-3 PUFAs during inflammatory responses elicited by gram-negative bacteria in macrophages, and in glial cells (astrocytes from control and ALS patients) submitted to redox stress conditions. Finally, in the fourth aim we will focus on macrophage Migration Inhibitor Factor (MIF) that recently regained attention due to its enigmatic and promiscuous role acting also as chaperone for SOD1 altering its aggregation path. Being abundantly present in many cells during health and disease, MIF also have pathogenic roles and drugs targeted to its inhibition are being tested. Here we aim to better understand the interplay between oxidized lipids and MIF. (AU)