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Aging and neuroprotection: effects of Klotho protein in energetic metabolism, Na,K-ATPase signaling and adaptative response in central nervous system

Grant number: 16/07427-8
Support Opportunities:Research Projects - Thematic Grants
Duration: March 01, 2017 - October 31, 2022
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: Bonnie Lynne Firestein-Miller ; Checler ; Daniel Charles Berwick ; Elisa Mitiko Kawamoto Iwashe ; Jacqueline Alves Leite ; Jiang Liu ; Karin Lykke-Hartmann ; Lucia da Conceição Andrade ; Paula Fernanda Kinoshita ; Tania Marcourakis
Associated scholarship(s):21/12906-0 - Evaluation of ouabain modulator function in central and peripheral inflammation in mixed asthma murine model., BP.DR
22/04708-7 - Evaluation of the effects of the cannabinoid agonist win- 55212-2 in the cell model of klotho deletion., BP.MS
+ associated scholarships 20/15353-0 - Evaluation of the effects of curcumin in hypomorphic mice for klotho, BP.MS
19/10044-1 - Study of the modulator role of Klotho protein in neuroinflammatory signaling in mice, BP.PD
18/14289-6 - The role of Klotho protein in Alzheimer's disease, BP.PD
19/05970-4 - Effects of ±-Klotho protein in TNF-± signaling through TNFR1 in glia primary culture, BP.IC
18/06953-3 - The role of Klotho in the uptake of glutamate in astrocytic primary culture, BP.IC
18/07896-3 - Effects of GPNMB pretein in the modulation of inflammatory processes induced by LPS in microglial cells and astrocytes rat cells, BP.MS - associated scholarships


The modulation of the glutamate activity via NMDA receptor has a strong influence in the adaptive processes that prevent premature aging, as well as play an important role in cognition and degenerative processes. It is well know that the insulin signaling pathways, mediators of the inflammatory response and Na,K-ATPase acting as enzyme and as a receiver of endogenous steroids (hormones with actions similar to ouabain) are associated with the modulation of the glutamate signaling in the brain. Recent studies in mammals has shown that low expression of Klotho protein displays premature aging phenotype, with a marked decrease in life expectancy in addition to the early onset of diseases and syndromes associated with aging, such as arteriosclerosis, osteoporosis, skin atrophy, pulmonary emphysema and cognitive decline, whereas its overexpression increases around 30% life expectancy. The Klotho protein is found in two forms: a coming form of Klotho gene, is present in the membrane (Beta-Klotho) acting as a required co-receptor for FGF23, while the secreted form (alpha-Klotho) acts as an endocrine regulator of diverse cell surface glycoproteins. The overall objective of this project is to investigate the actions of alfa-Klotho protein in energy metabolism and adaptive responses in the central nervous system, in order to understand their actions associated with signaling of insulin, inflammation, ouabain- Na,K-ATPase signaling, PTEN (Phosphatase and tensin homolog on chromosome ten) and autophagic processes. (AU)

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Scientific publications (15)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE MELLO, NATALIA PRUDENTE; ANDREOTTI, DIANA ZUKAS; ORELLANA, ANA MARIA; SCAVONE, CRISTOFORO; KAWAMOTO, ELISA MITIKO. Inverse sex-based expression profiles of PTEN and Klotho in mice. SCIENTIFIC REPORTS, v. 10, n. 1, . (11/21308-8, 16/07427-8, 16/22996-9, 15/25491-2)
VASCONCELOS, ANDREA RODRIGUES; DOS SANTOS, NILTON BARRETO; SCAVONE, CRISTOFORO; MUNHOZ, CAROLINA DEMARCHI. Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders. FRONTIERS IN PHARMACOLOGY, v. 10, . (16/07427-8, 12/24727-4)
ORELLANA, ANA MARIA; LEITE, JACQUELINE ALVES; KINOSHITA, PAULA FERNANDA; VASCONCELOS, ANDREA RODRIGUES; ANDREOTTA, DIANA ZUKAS; LIMA, LARISSA DE SA; XAVIER, GILBERTO FERNANDO; KAWAMOTO, ELISA MITIKO; SCAVONE, CRISTOFORO. Ouabain increases neuronal branching in hippocampus and improves spatial memory. Neuropharmacology, v. 140, p. 260-274, . (16/07427-8, 11/22844-0)
SAADE, MARINA; DE SOUZA, GIOVANNA ARAUJO; SCAVONE, CRISTOFORO; KINOSHITA, PAULA FERNANDA. The Role of GPNMB in Inflammation. FRONTIERS IN IMMUNOLOGY, v. 12, . (18/14289-6, 16/07427-8, 19/05970-4, 18/07896-3)
KAWAMOTO, E. M.; CARARO-LOPES, M. M.; KINOSHITA, P. F.; QUINTAS, L. E. M.; LIMA, L. S.; ANDREOTTI, D. Z.; SCAVONE, C.. Influence of Nitric Oxide-Cyclic GMP and Oxidative STRESS on Amyloid-beta Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices. Journal of Membrane Biology, v. 254, n. 5-6, SI, . (16/07427-8, 16/22996-9, 18/14289-6, 19/12974-6, 14/14199-6)
NAGY, GABRIELA SPINA; KAWAMOTO, ELISA MITIKO; BRIDI, JESSIKA CRISTINA. The role of PTEN signaling in synaptic function: Implications in autism spectrum disorder. Neuroscience Letters, v. 759, . (20/08005-5, 16/07427-8, 19/12974-6, 19/10044-1)
VASCONCELOS, ANDREA R.; DA PAIXAO, AMANDA G.; KINOSHITA, PAULA F.; ORELLANA, ANA M.; SCAVONE, CRISTOFORO; KAWAMOTO, ELISA M.. Toll-like Receptor 4 Signaling is Critical for the Adaptive Cellular Stress Response Effects Induced by Intermittent Fasting in the Mouse Brain. Neuroscience, v. 465, p. 142-153, . (14/01435-3, 19/12974-6, 16/22996-9, 16/07376-4, 06/57729-9, 16/07427-8, 11/12255-8, 09/11915-4)
CARARO-LOPES, MARINA MINTO; YOKOYAMA MAZUCANTI, CAIO HENRIQUE; SCAVONE, CRISTOFORO; KAWAMOTO, ELISA MITIKO; BERWICK, DANIEL CHARLES. The relevance of alpha-KLOTHO to the central nervous system: Some key questions. AGEING RESEARCH REVIEWS, v. 36, p. 137-148, . (16/07427-8, 13/10787-8, 14/14199-6, 11/21308-8)
LEITE, J. A.; ISAKSEN, T. J.; HEUCK, A.; SCAVONE, C.; LYKKE-HARTMANN, K.. The alpha(2) Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation. SCIENTIFIC REPORTS, v. 10, n. 1, . (16/07427-8, 16/21343-1, 14/10171-0)
YSHII, LIDIA M.; MANFIOLLI, ADRIANA O.; DENADAI-SOUZA, ALEXANDRE; KINOSHITA, PAULA F.; GOMES, MARCELO D.; SCAVONE, CRISTOFORO. Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway. IBRO REPORTS, v. 9, p. 218-223, . (12/07784-4, 11/10303-5, 14/24951-7, 09/12375-3, 18/01308-2, 16/07427-8, 19/10044-1, 18/14289-6, 13/22196-4)
MAZUCANTI, CAIO H.; KAWAMOTO, ELISA M.; MATTSON, MARK P.; SCAVONE, CRISTOFORO; CAMANDOLA, SIMONETTA. Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, v. 39, n. 8, p. 1544-1556, . (16/07427-8, 16/09971-7)
CRUNFLI, FERNANDA; MAZUCANTI, CAIO HENRIQUE; MACEDO DE MORAES, RUAN CARLOS; COSTA, ANDRESSA PEREIRA; RODRIGUES, ALICE CRISTINA; SCAVONE, CRISTOFORO; TORRAO, ANDREA DA SILVA. NO-Dependent Akt Inactivation by S-Nitrosylation as a Possible Mechanism of STZ-Induced Neuronal Insulin Resistance. JOURNAL OF ALZHEIMER'S DISEASE, v. 65, n. 4, p. 1427-1443, . (14/06372-0, 16/07427-8, 10/14090-3)
ANDREOTTI, DIANA ZUKAS; SILVA, JOSIANE DO NASCIMENTO; MATUMOTO, AMANDA MIDORI; ORELLANA, ANA MARIA; DE MELLO, PALOMA SEGURA; KAWAMOTO, ELISA MITIKO. Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies. FRONTIERS IN NUTRITION, v. 7, . (16/22996-9, 16/07427-8)
KINOSHITA, PAULA FERNANDA; MARQUES ORELLANA, ANA MARIA; NAKAO, VINICIUS WATANABE; DE SOUZA PORT'S, NATACHA MEDEIROS; MENEZES QUINTAS, LUIS EDUARDO; KAWAMOTO, ELISA MITIKO; SCAVONE, CRISTOFORO. The Janus face of ouabain in Na+/K+-ATPase and calcium signalling in neurons. British Journal of Pharmacology, . (16/22996-9, 19/12974-6, 16/07427-8, 18/14289-6)

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