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From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study

Grant number: 17/25588-1
Support Opportunities:Research Projects - Thematic Grants
Duration: February 01, 2019 - July 31, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Daniel Martins-de-Souza
Grantee:Daniel Martins-de-Souza
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Alessandro dos Santos Farias ; Andre Schwambach Vieira ; Andrea Schmitt ; Ary Gadelha de Alencar Araripe Neto ; Benilton de Sá Carvalho ; Emmanuel Dias-Neto ; Helder Takashi Imoto Nakaya ; Henrique Marques Barbosa de Souza ; Karina Diniz Oliveira ; Marcelo Alves da Silva Mori ; Marcus Bustamante Smolka ; Pedro Manoel Mendes de Moraes Vieira ; Peter Nilsson ; Rodrigo Affonseca Bressan ; Stevens Kastrup Rehen
Associated grant(s):20/04746-0 - Understanding the molecular bases and the role of risk factors associated to SARS-CoV-2 infection in preclinical models, AP.R
19/00098-7 - Multi-User Equipment approved in grant 2017/25588-1: cromatógrafo Acquity UPLC I-Class, AP.EMU
Associated scholarship(s):22/12693-0 - Neural cell culture, BP.TT
22/10140-3 - The role of 14-3-3 proteins in autophagy in the context of Schizophrenia, BP.PD
22/00227-4 - Expanding the dissemination of the project From basic understanding to clinical biomarkers for Schizophrenia, BP.JC
+ associated scholarships 21/03598-0 - Processing proteomic data using in silico systems biology to understand the molecular bases of schizophrenia treatment, BP.TT
20/09165-6 - Optimization of a quantitative proteomics platform for blood plasma samples analyses, BP.TT
20/08397-0 - Application of the Interfering RNA technique in oligodendrocytes aiming at the gene silencing of hnRNP C1 / C2 to study its role in schizophrenia, BP.TT
19/22398-2 - The role of cholesterol synthesis in the mode of action of clozapine in schizophrenia models, BP.PD
19/05155-9 - The role of the glycoproteome and phosphoproteome during neuronal differentiation in schizophrenia, BP.PD
18/03450-0 - Study of Metabolic Syndrome on clozapine treated adipocytes, BP.DR
19/05747-3 - Maintaining and maturing oligodendrocyte cell line, BP.TT - associated scholarships

Abstract

Schizophrenia is among the most disabling diseases of humankind, affecting 1% of the world's population (in Brazil, almost 2.5 million people are affected). One of the biggest hurdles faced by most patients is the poor efficacy of current antipsychotic medication. This stems from the lack of understanding of schizophrenia's pathobiology and the lack of biomarkers and biological mechanisms associated with a positive medication response. By employing state-of-the-art proteomics and lipidomics in blood plasma collected in vivo from patients before and after treatment, we aim to identify predictive biomarkers for medication response. These will be used to compose a mass spectrometry-based molecular assay to aid psychiatrists in predicting the likelihood of a successful treatment before initiating medication. This will be the first clinical test ever developed to determine medication response in psychiatry. Moreover, by analyzing the proteomes and lipidomes of these blood plasma samples, we can also better understand the biochemistry and biology involved the response. To develop new and more effective medication, we must increase our understanding of the molecular aspects of schizophrenia. Therefore, we will test several of the biological hypotheses our group has built over the past few years. For that, we are moving to a multidisciplinary approach employing CRISPR/Cas9, flow cytometry, proteomics, phosphoproteomics, lipidomics, interactomics, transcriptomics, and miRNA expression in coordination with several laboratories in Brazil and abroad to characterize postmortem brains and peripheral mononuclear blood cells from patients and mentally healthy controls. In addition, pre-clinical models will also be evaluated, such as induced pluripotent stem cell-derived neurons and glial cells, cerebral organoids, and cell lines of neurons, glia, and adipocytes. We will search for the validation of the key biological processes we found associated with schizophrenia such as tripartite synapses, spliceosomes, myelination, and energy pathway-associated alterations, as well as the role of the endocannabinoid system in glia. Results from these studies may point to biological processes that could be modulated by new drugs yet to be developed. Our results will lead to three major benefits in the field: 1) refining a biochemical assay able to predict the efficacy of medications currently available to patients, even before the treatment starts; 2) identifying key biochemical pathways associated with effective medication; 3) and better comprehension of schizophrenia's molecular basis and biochemistry, which is key for developing new treatments. Our project navigates from basic to applied science, towards the establishment of translational strategies driven by personalized and precision medicine concepts, helping to bring the bench closer to the bedside. (AU)

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Scientific publications (18)
(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)
BRANDAO-TELES, CAROLINE; DE ALMEIDA, VALERIA; CASSOLI, JULIANA S.; MARTINS-DE-SOUZA, DANIEL. Oligodendrocytes: Potential of Discovering New Treatment Targets. FRONTIERS IN PHARMACOLOGY, v. 10, . (17/25588-1, 14/14881-1, 15/23049-0, 17/18242-1, 14/10068-4)
ZUCCOLI, GIULIANA S.; REIS-DE-OLIVEIRA, GUILHERME; GARBES, BRUNA; FALKAI, PETER; SCHMITT, ANDREA; NAKAYA, I, HELDER; MARTINS-DE-SOUZA, DANIEL. Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, . (17/25588-1, 19/00098-7, 18/01410-1, 13/08216-2, 18/14666-4, 12/19278-6, 17/50137-3)
SILVA-COSTA, LICIA C.; GARCIA-ROSA, SHEILA; SMITH, BRADLEY J.; BALDASSO, PAULO A.; STEINER, JOHANN; MARTINS-DE-SOUZA, DANIEL. Blood plasma high abundant protein depletion unintentionally carries over 100 proteins. SEPARATION SCIENCE PLUS, . (13/08711-3, 17/25588-1, 16/07948-8, 18/03422-7, 14/10068-4, 19/05747-3)
GOUVEA-JUNQUEIRA, DANIELLE; FALVELLA, ANA CAROLINE BRAMBILLA; ANTUNES, ANDRE SARAIVA LEAO MARCELO; SEABRA, GABRIELA; BRANDAO-TELES, CAROLINE; MARTINS-DE-SOUZA, DANIEL; CRUNFLI, FERNANDA. Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia. FRONTIERS IN PSYCHIATRY, v. 11, . (17/25588-1, 17/25055-3, 18/03673-0, 19/22398-2, 18/10362-0, 18/25439-9)
RADAIC, ALLAN; MARTINS-DE-SOUZA, DANIEL. The state of the art of nanopsychiatry for schizophrenia diagnostics and treatment. Nanomedicine-Nanotechnology Biology and Medicine, v. 28, . (17/25588-1, 13/08711-3, 18/03673-0)
ZUCCOLI, GIULIANA S.; REIS-DE-OLIVEIRA, GUILHERME; GARBES, BRUNA; FALKAI, PETER; SCHMITT, ANDREA; NAKAYA, I, HELDER; MARTINS-DE-SOUZA, DANIEL. Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 271, n. 8, p. 1579-1586, . (18/01410-1, 17/25588-1, 13/08216-2, 19/00098-7, 12/19278-6, 17/50137-3, 18/14666-4)
MARTINS-DE-SOUZA, DANIEL; GUEST, PAUL C.; STEINER, JOHANN. A proteomic signature associated to atypical antipsychotic response in schizophrenia patients: a pilot study. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 270, n. 1, p. 127-134, . (17/25588-1, 13/08711-3)
GARCIA-ROSA, SHEILA; CARVALHO, BENILTON S.; GUEST, PAUL C.; STEINER, JOHANN; MARTINS-DE-SOUZA, DANIEL. Blood plasma proteomic modulation induced by olanzapine and risperidone in schizophrenia patients. JOURNAL OF PROTEOMICS, v. 224, . (17/25588-1, 14/10068-4, 16/18715-4)
REIS-DE-OLIVEIRA, G.; ZUCCOLI, G. S.; FIORAMONTE, M.; SCHIMITT, A.; FALKAI, P.; ALMEIDA, V; MARTINS-DE-SOUZA, D.. Digging deeper in the proteome of different regions from schizophrenia brains. JOURNAL OF PROTEOMICS, v. 223, . (17/25588-1, 18/14666-4, 18/03673-0, 17/18242-1, 19/00098-7, 16/18715-4, 18/01410-1, 14/10068-4)
FIORAMONTE, MARIANA; REIS-DE-OLIVEIRA, GUILHERME; BRANDAO-TELES, CAROLINE; MARTINS-DE-SOUZA, DANIEL. A glimpse on the architecture of hnRNP C1/C2 interaction network in cultured oligodendrocytes. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1869, n. 12, . (18/01410-1, 16/18715-4, 17/25588-1, 19/00098-7, 17/25055-3)
FALVELLA, ANA CAROLINE BRAMBILLA; SMITH, BRADLEY JOSEPH; SILVA-COSTA, LICIA C.; VALENCA, ALINE G. F.; CRUNFLI, FERNANDA; ZUARDI, ANTONIO W.; HALLAK, JAIME E.; CRIPPA, JOSE A.; ALMEIDA, VALERIA DE; MARTINS-DE-SOUZA, DANIEL. Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. FRONTIERS IN MOLECULAR NEUROSCIENCE, v. 14, . (18/03422-7, 08/09009-2, 17/18242-1, 19/00098-7, 17/25588-1, 19/22398-2, 18/10362-0, 18/03450-0, 18/03673-0)
MARTINS-DE-SOUZA, DANIEL. Mass Spectrometry-Based Proteomics to Understand Schizophrenia. BRAZILIAN JOURNAL OF ANALYTICAL CHEMISTRY, v. 7, n. 29, p. 13-17, . (17/25588-1)
SEABRA, GABRIELA; DE ALMEIDA, VALERIA; REIS-DE-OLIVEIRA, GUILHERME; CRUNFLI, FERNANDA; LEAO MARCELO ANTUNES, ANDRE SARAIVA; MARTINS-DE-SOUZA, DANIEL. Ubiquitin-proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia. SCIENTIFIC REPORTS, v. 10, n. 1, . (19/22398-2, 17/25588-1, 14/10068-4, 17/18242-1, 19/03271-1, 19/00098-7, 18/03673-0)
MARTINS-DE-SOUZA, DANIEL; GUEST, PAUL C.; REIS-DE-OLIVEIRA, GUILHERME; SCHMITT, ANDREA; FALKAI, PETER; TURCK, CHRISTOPH W.. An overview of the human brain myelin proteome and differences associated with schizophrenia. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, v. 22, n. 4, . (19/00098-7, 18/01410-1, 17/25588-1)
DIAS, THOMAZ LUSCHER; SCHUCH, VIVIANE; BALEEIRO BELTRAO-BRAGA, PATRICIA CRISTINA; MARTINS-DE-SOUZA, DANIEL; BRENTANI, HELENA PAULA; FRANCO, GLORIA REGINA; NAKAYA, HELDER IMOTO. Drug repositioning for psychiatric and neurological disorders through a network medicine approach. TRANSLATIONAL PSYCHIATRY, v. 10, n. 1, . (17/25588-1, 18/03673-0, 14/10068-4, 19/00098-7, 18/16748-8)
VELASQUEZ, ERIKA; MARTINS-DE-SOUZA, DANIEL; VELASQUEZ, INGRID; ALVES CARNEIRO, GABRIEL REIS; SCHMITT, ANDREA; FALKAI, PETER; DOMONT, GILBERTO B.; NOGUEIRA, FABIO C. S.. Quantitative Subcellular Proteomics of the Orbitofrontal Cortex of Schizophrenia Patients. JOURNAL OF PROTEOME RESEARCH, v. 18, n. 12, SI, p. 4240-4253, . (17/25588-1, 19/00098-7)
DE ALMEIDA, VALERIA; ALEXANDRINO, GUILHERME L.; AQUINO, ADRIANO; GOMES, ALEXANDRE F.; MURGU, MICHAEL; DOBROWOLNY, HENRIK; GUEST, PAUL C.; STEINER, JOHANN; MARTINS-DE-SOUZA, DANIEL. Changes in the blood plasma lipidome associated with effective or poor response to atypical antipsychotic treatments in schizophrenia patients. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 101, . (17/25588-1, 15/08201-0, 14/10068-4, 17/18242-1, 15/09159-8, 19/00098-7)
SANTOS DE OLIVEIRA, PERCILLIA VICTORIA; GARCIA-ROSA, SHEILA; AZEVEDO SACHETTO, ANA TERESA; SOARES MORETTI, ANA IOCHABEL; DEBBAS, VICTOR; DE BESSA, TIPHANY CORALIE; SILVA, NATHALIA TENGUAN; PEREIRA, ALEXANDRE DA COSTA; MARTINS-DE-SOUZA, DANIEL; SANTORO, MARCELO LARAMI; et al. Protein disulfide isomerase plasma levels in healthy humans reveal proteomic signatures involved in contrasting endothelial phenotypes. REDOX BIOLOGY, v. 22, . (17/25588-1, 18/07511-4, 17/19866-9, 14/20595-1, 13/08711-3, 13/25177-0, 14/10068-4, 13/07937-8)

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