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Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases

Grant number: 21/06009-6
Support Opportunities:Research Projects - Thematic Grants
Duration: November 01, 2022 - October 31, 2027
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Cristoforo Scavone
Grantee:Cristoforo Scavone
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
Elisa Mitiko Kawamoto Iwashe
Associated researchers:Alline Cristina de Campos ; Ana Maria Marques Orellana ; Bonnie Lynne Firestein-Miller ; Checler ; Daniel Charles Berwick ; Diana Zukas Andreotti Viana ; Jacqueline Alves Leite ; Juan-Carlos Leza ; Karin Lykke-Hartmann ; Leandro Augusto de Oliveira Barbosa ; Lucia da Conceição Andrade ; Luis Eduardo Menezes Quintas ; Marcus Vinícius de Souza João Luiz ; Paula Fernanda Kinoshita ; Rosilene Motta Elias Coelho ; Sandra Rodrigues Mascarenhas ; Tatiana Rosado Rosenstock
Associated grant(s):23/01570-7 - The effects of glucocorticoids in in vitro models of the blood-brain barrier facing an inflammatory challenge., AP.R
Associated scholarship(s):23/09814-2 - Identification of the relationship between the thermodynamic signature of the kinetics of cardiotonic steroids and their cellular effects, BP.PD
22/15514-9 - Possible changes in the expression of klotho protein in the hippocampus, cortex and cerebellum of mice, due to prenatal exposure to valproic acid, BP.MS
23/15535-9 - Evaluation of physical exercise effects on cognitive impairment induced by nefrectomy in mice, BP.DR
+ associated scholarships 24/05200-2 - Evaluation of the modulating function of ouabain in central and peripheral inflammation in a murine model of asthma, BP.TT
23/01789-9 - OUABAIN EFFECTS ON CHANGES IN MITOCHONDRIAL FUNCTION AND THE NEUROGENESIS PROCESS IN CORTICAL NEURONAL CELLS EXPOSED TO ROTENONE, BP.IC
22/13996-6 - Evaluation of the effects of BD-15 on hippocampal neurogenesis, BP.MS
22/13804-0 - Evaluation of the expression of proteins involved in synaptic function and plasticity in Klotho-hypomorphic mice, BP.IC - associated scholarships

Abstract

Our previous data revealed that the signaling pathways associated with ±-Klotho, glutamate, mediators of the inflammatory response in the central nervous system (CNS) and that related to different isoforms of the Na, K-ATPase (NKA) protein as a pump and receptor for endogenous steroids ( ouabain-like hormones) are associated with neuroplasticity and neuroprotection. This effect induced by pharmacologic (cardiosteroids, Klotho, Curcumin, PTEN (Phosphatase and Tensin Homolog on Chromosome Ten), Rotenone (an electron transport chain complex I inhibitor), cannabinoid receptor inverse agonist (CB1), GPNMB (glycoprotein nonmetastatic melanoma protein B), and by non-pharmacologic strategies (intermittent fasting, physical exercise) involves glial and neuronal cell crosstalk through activation of different intracellular pathways involving mediators, such as glutamate and cytokines, transcription factors, and gene expression which will exert a marked influence on the adaptive processes (neuroplasticity) that prevent premature aging, in addition to playing an essential role in cognition and neurodegenerative processes. The general objective is to continue evaluating the effect of these agents on the CNS (FAPESP Process 2016/07427-8) exploring changes in neuroplasticity -induced by these mediators in the presence of a modified expression or signaling of the ±-Klotho, and of the isoforms of NKA. The studies involve in vitro approaches using models of neuronal and glial cells, as well as in vivo studies with a behavioral and biochemical approach in the presence (or absence) of changes in the expression of these proteins (by using vectors, interference RNA, transgenic animals with specific protein modified expression), in different models of inflammation (obesity and asthma), and in Hemodialysis Patients. Finally, there are perspectives of approaching molecular, morphological, and functional changes in the cortical neurons of patients through the induction of pluripotent stem cells (iPSCs) that helps to unravel the mechanisms involved with the emergence of cognitive decline as revealed in previous studies of our groups associated with chronic kidney disease aiming to discover possible pharmacological targets and biological markers. (AU)

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