Role of the enzyme Pyruvate Kinase M2 (PKM2) in astrocytes under neuroinflammatory conditions

• Grant number: 23/13328-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2024
• End date: July 31, 2027
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Larissa Pinto de Andrade
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Astrocytes are the glial cells present in greatest quantity in the Central Nervous System (CNS) and have been increasingly described as important components in homeostatic and pathological conditions. Among some situations, these cells are known to play a major role in the development of neuroinflammatory diseases. Given the highly energetic profile of astrocytes, these cells have the ability to alter their own metabolism in cases of system dysfunction, so that brain homeostasis is maintained. The glycolysis pathway is the main pathway through which glucose oxidation is carried out, and, as a final fact, pyruvate catalysis and ATP formation occur through the action of the enzyme Pyruvate Kinase (PK). After this stage, under anaerobic conditions, pyruvate can be used as a substrate for the formation of lactate, a metabolite widely described as important in controlling CNS homeostasis. PKM2 is found in four isoforms in mammals, with the M2 isoform (PKM2) being described as important in the development of inflammatory conditions. Since the literature demonstrates that both immune cells and CNS resident cells undergo metabolic changes in the face of worsening, the objective of the present work is to evaluate the role of PKM2 in astrocytes in modulating astrocytic activation in neuroinflammatory conditions. Preliminary results from our group demonstrate that animals deficient in PKM2 specifically in astrocytes present a worsening on development of Experimental Autoimmune Encephalomyelitis, which suggests a possible antiinflammatory role for these enzymes in these glial cells. In this regard, our study will focus on the potential role of the PKM2-pyruvate-lactate axis for these antiinflammatory effects, through both autocrine and paracrine mechanisms. For this purpose, in vitro and in vivo techniques will be used, as well as pharmacological and genetic modulations of astrocytes to evaluate the role of PKM2 in neuroinflammation.