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Developing a predictive test for a successful medication response and understanding the molecular bases of schizophrenia through proteomics

Grant number: 13/08711-3
Support type:Research Grants - Young Investigators Grants
Duration: February 01, 2014 - July 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Daniel Martins-de-Souza
Grantee:Daniel Martins-de-Souza
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas, SP, Brazil
Associated grant(s):14/10068-4 - Multi-User Equipment approved in grant 13/08711-3: mass spectrometer waters SYNAPT G2-Si HDMS + nanoACQUITY UPLC, AP.EMU
Associated scholarship(s):17/18242-1 - Biochemical pathways affected by cannabinoid drugs of human oligodendrocytes, BP.PD
16/18715-4 - Establishment of the hnRNPs role on schizophrenia through protein interaction network mapping, BP.PD
17/00025-4 - Establishment of selected reaction monitoring (SRM) technique for proteins of interest in schizophrenia, BP.IC
+ associated scholarships 16/07948-8 - Relationship between a myelin-associated phosphodiesterase CNP and schizophrenia, BP.MS
16/04912-2 - Characterization of the mitochondrial proteome and oxidative biochemical profile of neural cells derived from iPSCs from patients with schizophrenia, BP.MS
16/07332-7 - The role of 14-3-3 and Ephrin signaling pathways on cellular communication between neurons-astrocytes and the functioning of the synapse tripartite, BP.DR
15/23049-0 - Employing human oligodendroglial cell cultures and glutamatergic dysfunction to understand the molecular basis of schizophrenia, BP.MS
15/09159-8 - Development of lipidomic platform to studies and their use in the assessment of response to antipsychotics in patients with schizophrenia, BP.PD
14/21035-0 - Quantitative proteomics in neural cell lines and organoids derived from induced pluripotent stem cells from schizophrenia patients, BP.PD
14/14881-1 - Understanding the influence of glycolysis components in the function of oligodendrocytes: linking with findings in schizophrenia, BP.PD
13/25702-8 - Developing a predictive test for a successful medication response and understanding the molecular bases of schizophrenia through proteomics, BP.JP - associated scholarships

Abstract

Schizophrenia is an incurable and debilitating mental disorder which affects approximately 1% of world population. It is a multifactorial disease involving exogenous and endogenous factors since the neurodevelopment. The molecular mechanisms of the disease are still to be unraveled for an integrated comprehension of the pathobiology. Additionally, biomarkers for diagnosis and for the likelihood of a successful treatment are not existent. Proteomics is, by definition, a suitable tool for investigating multifactorial disorders as schizophrenia. Proteins differentially expressed identified in a given biological condition may pinpoint which pathways are altered leading to a better comprehension of the disorder, and can be used as potential biomarker candidates. This project will perform a pioneer proteome analyses of plasma collected in vivo from patients and controls before and after medication. Our main goals are unraveling biochemical pathways modulated by the medication as well as revealing for the first time proteins that can act as potential biomarkers, which may indicate the likelihood of a successful treatment. Biomarker candidates will be combined in a mass spectrometry-based molecular assay to be evaluated as the first clinical test ever to determine medication response. Furthermore, we intend to contribute in the comprehension of the molecular aspects of schizophrenia. Based in our previous results, we will investigate the sub-proteomes of gray and white matter of four different brain regions from postmortem brains of schizophrenia patients and controls as well as preclinical models such as cultured oligodendrocytes. Our objective is to reveal differentially expressed proteins and their biochemical pathways for understanding their role in the establishment and maintenance of schizophrenia. This project will shed light in the comprehension of the molecular bases of schizophrenia and goes towards the development of a personalized medicine strategy with potential clinical implementation. (AU)

Articles published in Agência FAPESP about the research grant
Novel methodology increases resolution in oligodendrocyte proteomics 
Nova metodologia aumenta a resolução em análises de conjuntos de proteínas 
Study associates schizophrenia with defective processing of messenger RNA in cells 
New targets for treatment of schizophrenia 
Research paves the way for a new treatment against schizophrenia 
Articles published in Revista Pesquisa FAPESP about the project
Depression due to inflammation 

Scientific publications (25)
(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)
AQUINO, ADRIANO; ALEXANDRINO, GUILHERME L.; GUEST, PAUL C.; AUGUSTO, FABIO; GOMES, ALEXANDRE F.; MURGU, MICHAEL; STEINER, JOHANN; MARTINS-DE-SOUZA, DANIEL. Blood-Based Lipidomics Approach to Evaluate Biomarkers Associated With Response to Olanzapine, Risperidone, and Quetiapine Treatment in Schizophrenia Patients. FRONTIERS IN PSYCHIATRY, v. 9, MAY 25 2018. Web of Science Citations: 0.
VELASQUEZ, ERIKA; NOGUEIRA, FABIO C. S.; VELASQUEZ, INGRID; SCHRNITT, ANDREA; FALKAI, PETER; DOMONT, GILBERTO B.; MARTINS-DE-SOUZA, DANIEL. Synaptosomal Proteome of the Orbitofrontal Cortex from Schizophrenia Patients Using Quantitative Label-Free and iTRAQ-Based Shotgun Proteomics. JOURNAL OF PROTEOME RESEARCH, v. 16, n. 12, p. 4481-4494, DEC 2017. Web of Science Citations: 3.
CASSOLI, JULIANA S.; BRANDAO-TELES, CAROLINE; SANTANA, ALINE G.; SOUZA, GUSTAVO H. M. F.; MARTINS-DE-SOUZA, DANIEL. Ion Mobility-Enhanced Data-Independent Acquisitions Enable a Deep Proteomic Landscape of Oligodendrocytes. PROTEOMICS, v. 17, n. 21 NOV 2017. Web of Science Citations: 1.
DAKIC, VANJA; NASCIMENTO, JULIANA MINARDI; SARTORE, RAFAELA COSTA; MACIEL, RENATA DE MORAES; DE ARAUJO, DRAULIO B.; RIBEIRO, SIDARTA; MARTINS-DE-SOUZA, DANIEL; REHEN, STEVENS K. Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. SCIENTIFIC REPORTS, v. 7, OCT 9 2017. Web of Science Citations: 2.
ZUCCOLI, GIULIANA S.; SAIA-CEREDA, VERONICA M.; NASCIMENTO, JULIANA M.; MARTINS-DE-SOUZA, DANIEL. The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. FRONTIERS IN NEUROSCIENCE, v. 11, SEP 7 2017. Web of Science Citations: 1.
TURCK, CHRISTOPH W.; GUEST, PAUL C.; MACCARRONE, GIUSEPPINA; ISING, MARCUS; KLOIBER, STEFAN; LUCAE, SUSANNE; HOLSBOER, FLORIAN; MARTINS-DE-SOUZA, DANIEL. Proteomic Differences in Blood Plasma Associated with Antidepressant Treatment Response. FRONTIERS IN MOLECULAR NEUROSCIENCE, v. 10, AUG 31 2017. Web of Science Citations: 0.
DEZONNE, ROMULO SPERDUTO; SARTORE, RAFAELA COSTA; NASCIMENTO, JULIANA MINARDI; SAIA-CEREDA, VERONICA M.; ROMAO, LUCIANA FERREIRA; ALVES-LEON, SONIZA VIEIRA; DE SOUZA, JORGE MARCONDES; MARTINS-DE-SOUZA, DANIEL; REHEN, STEVENS KASTRUP; ALCANTARA GOMES, FLVIA CARVALHO. Derivation of Functional Human Astrocytes from Cerebral Organoids. SCIENTIFIC REPORTS, v. 7, MAR 27 2017. Web of Science Citations: 2.
SAIA-CEREDA, VERONICA M.; CASSOLI, JULIANA S.; MARTINS-DE-SOUZA, DANIEL; NASCIMENTO, JULIANA M. Psychiatric disorders biochemical pathways unraveled by human brain proteomics. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 267, n. 1, p. 3-17, FEB 2017. Web of Science Citations: 4.
GARCEZ, PATRICIA P.; NASCIMENTO, JULIANA MINARDI; DE VASCONCELOS, JANAINA MOTA; DA COSTA, RODRIGO MADEIRO; DELVECCHIO, RODRIGO; TRINDADE, PABLO; LOIOLA, ERICK CORREIA; HIGA, LUIZA M.; CASSOLI, JULIANA S.; VITORIA, GABRIELA; SEQUEIRA, PATRICIA C.; SOCHACKI, JAROSLAW; AGUIAR, RENATO S.; FUZII, HELLEN THAIS; BISPO DE FILIPPIS, ANA M.; GONCALVES VIANEZ JUNIOR, JOAO LIDIO DA SILVA; TANURI, AMILCAR; MARTINS-DE-SOUZA, DANIEL; REHEN, STEVENS K. Zika virus disrupts molecular fingerprinting of human neurospheres. SCIENTIFIC REPORTS, v. 7, JAN 23 2017. Web of Science Citations: 5.
CAFE-MENDES, C. C.; FERRO, E. S.; TORRAO, A. S.; CRUNFLI, F.; RIOLI, V.; SCHMITT, A.; FALKAI, P.; BRITTO, L. R.; TURCK, C. W.; MARTINS-DE-SOUZA, D. Peptidomic analysis of the anterior temporal lobe and corpus callosum from schizophrenia patients. JOURNAL OF PROTEOMICS, v. 151, n. SI, p. 97-105, JAN 16 2017. Web of Science Citations: 6.
TAVARES, RAPHAEL; WAJNBERG, GABRIEL; SCHERER, NICOLE DE MIRANDA; PAULETTI, BIANCA ALVES; CASSOLI, JULIANA S.; FERREIRA, CARLOS GIL; PAES LEME, ADRIANA FRANCO; DE ARAUJO-SOUZA, PATRICIA SAVIO; MARTINS-DE-SOUZA, DANIEL; PASSETTI, FABIO. Unveiling alterative splice diversity from human oligodendrocyte proteome data. JOURNAL OF PROTEOMICS, v. 151, n. SI, p. 293-301, JAN 16 2017. Web of Science Citations: 0.
SCHMITT, ANDREA; MARTINS-DE-SOUZA, DANIEL; AKBARIAN, SCHAHRAM; CASSOLI, JULIANA S.; EHRENREICH, HANNELORE; FISCHER, ANDRE; FONTEH, ALFRED; GATTAZ, WAGNER F.; GAWLIK, MICHAEL; GERLACH, MANFRED; GRUNBLATT, EDNA; HALENE, TOBIAS; HASAN, ALKOMIET; HASHIMOTO, KENIJ; KIM, YONG-KU; KIRCHNER, SOPHIE-KATHRIN; KORNHUBER, JOHANNES; KRAUS, THEO F. J.; MALCHOW, BEREND; NASCIMENTO, JULIANA M.; ROSSNER, MORITZ; SCHWARZ, MARKUS; STEINER, JOHANN; TALIB, LEDA; THIBAUT, FLORENCE; RIEDERER, PETER; FALKAI, PETER; FORCE, MEMBERS WFSBP TASK. Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia, part III: Molecular mechanisms. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, v. 18, n. 5, p. 330-356, 2017. Web of Science Citations: 0.
NASCIMENTO, JULIANA M.; GARCIA, SHEILA; SAIA-CEREDA, VERONICA M.; SANTANA, ALINE G.; BRANDAO-TELES, CAROLINE; ZUCCOLI, GIULIANA S.; JUNQUEIRA, DANIELLE G.; REIS-DE-OLIVEIRA, GUILHERME; BALDASSO, PAULO A.; CASSOLI, JULIANA S.; MARTINS-DE-SOUZA, DANIEL. Proteomics and molecular tools for unveiling missing links in the biochemical understanding of schizophrenia. PROTEOMICS CLINICAL APPLICATIONS, v. 10, n. 12, SI, p. 1148-1158, DEC 2016. Web of Science Citations: 2.
SAIA-CEREDA, VERONICA M.; CASSOLI, JULIANA S.; SCHMITT, ANDREA; FALKAI, PETER; MARTINS-DE-SOUZA, DANIEL. Differential proteome and phosphoproteome may impact cell signaling in the corpus callosum of schizophrenia patients. SCHIZOPHRENIA RESEARCH, v. 177, n. 1-3, p. 70-77, NOV 2016. Web of Science Citations: 7.
VENDRAMINI, PEDRO H.; GATTAZ, WAGNER F.; SCHMITT, ANDREA; FALKAI, PETER; EBERLIN, MARCOS N.; MARTINS-DE-SOUZA, DANIEL. Pioneering ambient mass spectrometry imaging in psychiatry: Potential for new insights into schizophrenia. SCHIZOPHRENIA RESEARCH, v. 177, n. 1-3, p. 67-69, NOV 2016. Web of Science Citations: 4.
GUEST, PAUL C.; GUEST, FRANCESCA L.; MARTINS-DE SOUZA, DANIEL. Making Sense of Blood-Based Proteomics and Metabolomics in Psychiatric Research. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 19, n. 6 JUN 2016. Web of Science Citations: 14.
CASSOLI, JULIANA S.; GUEST, PAUL C.; SANTANA, ALINE G.; MARTINS-DE-SOUZA, DANIEL. Employing proteomics to unravel the molecular effects of antipsychotics and their role in schizophrenia. PROTEOMICS CLINICAL APPLICATIONS, v. 10, n. 4, SI, p. 442-455, APR 2016. Web of Science Citations: 3.
CASSOLI, JULIANA S.; IWATA, KEIKO; STEINER, JOHANN; GUEST, PAUL C.; TURCK, CHRISTOPH W.; NASCIMENTO, JULIANA M.; MARTINS-DE-SOUZA, DANIEL. Effect of MK-801 and Clozapine on the Proteome of Cultured Human Oligodendrocytes. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 10, MAR 3 2016. Web of Science Citations: 11.
MARTINS-DE-SOUZA, DANIEL; CASSOLI, JULIANA S.; NASCIMENTO, JULIANA M.; HENSLEY, KENNETH; GUEST, PAUL C.; PINZON-VELASCO, ANDRES M.; TURCK, CHRISTOPH W. The protein interactome of collapsin response mediator protein-2 (CRMP2/DPYSL2) reveals novel partner proteins in brain tissue. PROTEOMICS CLINICAL APPLICATIONS, v. 9, n. 9-10, SI, p. 817-831, OCT 2015. Web of Science Citations: 9.
SAIA-CEREDA, VERONICA M.; CASSOLI, JULIANA S.; SCHMITT, ANDREA; FALKAI, PETER; NASCIMENTO, JULIANA M.; MARTINS-DE-SOUZA, DANIEL. Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 265, n. 7, p. 601-612, OCT 2015. Web of Science Citations: 22.
GUEST, PAUL C.; IWATA, KEIKO; KATO, TAKAHIRO A.; STEINER, JOHANN; SCHMITT, ANDREA; TURCK, CHRISTOPH W.; MARTINS-DE-SOUZA, DANIEL. MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 9, MAY 12 2015. Web of Science Citations: 12.
STEINER, JOHANN; MARTINS-DE-SOUZA, DANIEL; SCHILTZ, KOLJA; SARNYAI, ZOLTAN; WESTPHAL, SABINE; ISERMANN, BEREND; DOBROWOLNY, HENRIK; TURCK, CHRISTOPH W.; BOGERTS, BERNHARD; BERNSTEIN, HANS-GERT; HORVATH, TAMAS L.; SCHILD, LORENZ; KEILHOFF, GERBURG. Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 8, NOV 18 2014. Web of Science Citations: 10.
OLIVEIRA, BRUNO M.; COORSSEN, JENS R.; MARTINS-DE-SOUZA, DANIEL. 2DE: The Phoenix of Proteomics. JOURNAL OF PROTEOMICS, v. 104, n. SI, p. 140-150, JUN 2 2014. Web of Science Citations: 39.
STEINER, JOHANN; SCHMITT, ANDREA; SCHROETER, MATTHIAS L.; BOGERTS, BERNHARD; FALKAI, PETER; TURCK, CHRISTOPH W.; MARTINS-DE-SOUZA, DANIEL. S100B is downregulated in the nuclear proteome of schizophrenia corpus callosum. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 264, n. 4, p. 311-316, JUN 2014. Web of Science Citations: 8.
MARTINS-DE-SOUZA, DANIEL. Proteomics, metabolomics, and protein interactomics in the characterization of the molecular features of major depressive disorder. DIALOGUES IN CLINICAL NEUROSCIENCE, v. 16, n. 1, p. 63-73, MAR 2014. Web of Science Citations: 28.

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