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The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg)

Grant number: 19/19435-3
Support type:Research Projects - Thematic Grants
Duration: February 01, 2020 - January 31, 2025
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Cooperation agreement: Netherlands Organisation for Scientific Research (NWO)
Principal researcher:Carlos Frederico Martins Menck
Grantee:Carlos Frederico Martins Menck
Principal researcher abroad: Erik Biessen
Institution abroad: Maastricht University, Maastricht (UM), Netherlands
Principal researcher abroad: Ingrid van der Pluijm
Institution abroad: Erasmus University Rotterdam (EUR), Netherlands
Principal researcher abroad: Jan H J Hoeijmakers
Institution abroad: Erasmus University Rotterdam (EUR), Netherlands
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
Niels Olsen Saraiva Câmara ; Pedro Manoel Mendes de Moraes Vieira ; Rodrigo da Silva Galhardo
Assoc. researchers:Armando Morais Ventura ; Clarissa Ribeiro Reily Rocha ; José Antonio Sanches Junior ; Juliana de Souza Almeida Aranha Camargo ; Lilian Kelly Faria Licariao Rocha ; Luciana Rodrigues Gomes ; Luís Marcelo Aranha Camargo ; Maria Isabel Alves de Souza Waddington Achatz ; Pio Colepicolo Neto ; Veridiana Munford
Associated grant(s):20/08876-6 - Multi-User Equipment approved with the Grant 2019/19435-3: GLOMAX Luminometer, AP.EMU
Associated scholarship(s):22/02311-2 - Cultivation of human cells with deficiencies in DNA repair under conditions other than atmospheric oxygen, BP.DD
22/02400-5 - Evaluation of metabolic alterations in human cells from patients with Trichothiodystrophy with deficiency in nucleotide excision repair, BP.IC
21/01398-4 - Assessment of DNA Damage Response Genes Under Different Environmental Conditions, BP.DR
+ associated scholarships 21/11455-5 - Technical support for bacterial and human cell culture, BP.TT
20/15371-8 - Role of pol º e pol ¹¹ translesion synthesis polymerases in cell replication and survival after irradiation with UVC light, BP.MS
20/02836-2 - Mechanisms of Glioblastoma resistance to antitumoral temozolomide in cells cultured as three-dimensional (3D) multicellular tumor spheroids in vitro: the role of translesion synthesis polymerases, BP.PD
20/12560-4 - Genotoxic effects after exposure of cells with deficiencies in DNA repair to blue light, BP.PD
21/09294-3 - Impact of post-translational protein modifications on human cells with genome damage and cell transformation, BP.PD
21/03182-9 - Interface among DNA repair, metabolism and the inflammatory immune response, BP.PD
21/01420-0 - Study of the role of mitochondrial dynamics in the activation of macrophages, BP.DD
20/15399-0 - Study of the role of mitochondria dynamics in obesity-induced inflammation, BP.PD
20/12744-8 - Genomic and genetic analysis of SOS response induction in Pseudomonas aeruginosa, BP.DD
17/14833-5 - Nucleotide excision repair roles in R-loops accumulation and telomere maintenance in human cells, BP.PD
16/25784-2 - Resistance mechanisms to treatment with temozolomide in glioma cells, BP.PD
17/01760-0 - Investigating the involvement of genome lesions and DNA repair in cells infected by Trypanosoma cruzi, BP.PD - associated scholarships

Abstract

The world population is getting older and older. Unfortunately, this increased life expectancy is generally associated by so-called age-related vascular diseases, such as dementia, heart infarct, and stroke, which profoundly compromise the quality of life of the elderly. Age-related disorders are generally viewed as necessary evil. Our project challenges this dogma, as we propose that the aforementioned age-related disorders, despite their very diverse symptom profiles, share vascular ageing as common denominator. Moreover vascular ageing is caused by cumulative by accumulation of unrepaired DNA damage and mitochondrial dysfunction in the vessel wall which both increase with age. These events interplay and induce progressive senescence, inflammation and function loss of the vessel wall, which eventually will manifest as cardiovascular dysfunction or neurodegeneration, two very important hallmarks of ageing. Several of the predominant human diseases, such as obesity, diabetes and cardiovascular diseases, are directly related to this chain of cellular and physiological events that are part of and accelerate the process of ageing. This project joins experts on DNA damage repair, mitochondrial dysfunction, inflammation and cardiovascular disease to deploy and share knowledge and knowhow to unravel this common disease axis. To do so they will combine cutting edge technologies (e.g. scRNASEq, MitoNGS. CRISPR-Cas, organoids, MacroScreen functionomics platform, (intravital or multispectral) imaging and process reporters) with unique cellular and mouse models, deficient in processes that lead to accelerated ageing phenotypes. The insights gained in this project will be harnessed to the design of new (metabolic) biomarkers of vascular ageing and for novel therapeutic measures to revert this deleterious axis. By targeting a unique common mechanism in vascular ageing we expect that this project will help to reduce these age-related diseases thus improving quality of life for the elderly, and bringing the vista of healthy ageing within reach. Among the hypothesis raised to explain the ageing processes, the accumulation of unrepaired DNA damage during life is one of the main explanations and supported by many evidence. In a second part of the project we will investigate several aspects of DNA repair mechanisms and how unrepaired DNA damage may cause aging and cancer. In most of our studies we will use human cells with deficiencies in DNA repair processes, mainly derived from xeroderma pigmentosum (XP) and Cockayne syndrome (CS) patients. Cells from these patients will be employed in order to investigate mutagenesis by DNA damaging agents, including UVA and UVB. Mutations in XP Brazilian patients will also be identified, aiming to know the distribution of these mutations in the country. Also, the DNA damaging action of certain chemotherapeutic drugs drive us to investigate mechanisms of tumor cell resistance to treatments. A pioneer work to investigate how intracellular parasites affect host cells' genome metabolism, including DNA repair, will focus the parasite Trypanosoma cruzi and the human respiratory syncytial virus. Finally, DNA repair processes are extremely conserved, existing in virtually all life forms. The biological processes of defense against DNA damage in prokaryotes will also be studied in model bacteria. DNA damage responses will also be studied in samples from the Antarctic continent, understand responses in extreme environments. We hope these more general studies will help us to contribute to the understanding of the aging process, investigated in first part of this project. (AU)

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Scientific publications (16)
(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)
CASTRO, LIGIA PEREIRA; BATISTA-VIEIRA, DANILO; DE SOUZA, TIAGO ANTONIO; TIMOTEO, ANA RAFAELA DE SOUZA; COUTINHO, JESSICA DAYANNA LANDIVAR; PINHEIRO DE ALMEIDA, ISABEL CRISTINA; HENRIQUES, SHEILA RAMOS DE MIRANDA; AZEVEDO, FABIO MEDEIROS DE; ROSA, REGINALDO CRUZ ALVES; KANNOUCHE, PATRICIA L.; et al. PC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazi. FRONTIERS IN GENETICS, v. 12, . (19/19435-3, 13/08028-1)
ANDRADE-TOMAZ, MARINA; DE SOUZA, IZADORA; RIBEIRO REILY ROCHA, CLARISSA; RODRIGUES GOMES, LUCIANA. The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer. CELLS, v. 9, n. 9, . (13/07467-1, 19/21745-0, 19/19435-3)
DAVANZO, GUSTAVO GASTAO; CASTRO, GISELE; MORAES-VIEIRA, PEDRO MANOEL M.. Immunometabolic regulation of adipose tissue resident immune cells. CURRENT OPINION IN PHARMACOLOGY, v. 58, p. 44-51, . (19/19435-3, 19/25973-8, 15/15626-8, 16/18031-8)
FONTES PEREIRA, THAIS DOS SANTOS; CASTRO, LIGIA PEREIRA; MARTINS MENCK, CARLOS FREDERICO; THOMAZ MAIA, MARIA HELENA; DE SOUZA, LUCAS LACERDA; FONSECA, FELIPE PAIVA; REBELO PONTES, HELDER ANTONIO; CORREA PONTES, FLAVIA SIROTHEAU; GOMEZ, RICARDO SANTIAGO. eroderma pigmentosum variant: squamous cell carcinoma of the lower lip harboring exon 11 mutation of POLH. ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY, v. 132, n. 3, p. E97-E105, . (19/19435-3)
ALVES, NILMARA DE OLIVEIRA; PEREIRA, GUILHERME MARTINS; DI DOMENICO, MARLISE; COSTANZO, GIOVANNA; BENEVENUTO, SARAH; FONOFF, ADRIANA M. DE OLIVEIRA; XAVIER COSTA, NATALIA DE SOUZA; RIBEIRO, JR., GABRIEL; KAJITANI, GUSTAVO SATORU; MORENO, NATALIA CESTARI; et al. Inflammation response, oxidative stress and DNA damage caused by urban air pollution exposure increase in the lack of DNA repair XPC protein. Environment International, v. 145, . (17/17047-0, 19/19435-3, 13/21728-2)
LIMA-SILVA, LINCON FELIPE; LEE, JENNIFER; MORAES-VIEIRA, PEDRO M.. Soluble Carrier Transporters and Mitochondria in the Immunometabolic Regulation of Macrophages. Antioxidants & Redox Signaling, . (13/07607-8, 19/19435-3, 19/25973-8, 15/15626-8)
MARGARITA CUTINO-JIMENEZ, ANIA; MARTINS MENCK, CARLOS FREDERICO; CAMBAS, YUSDIEL TORRES; DIAZ-PEREZ, JUAN CARLOS. Protein signatures to identify the different genera within the Xanthomonadaceae family. Brazilian Journal of Microbiology, v. 51, n. 4, . (19/19435-3)
FLORENTINO, V, PILAR T.; MENDES, DAVI; VITORINO, FRANCISCA NATHALIA L.; MARTINS, DAVI J.; CUNHA, JULIA P. C.; MORTARA, RENATO A.; MENCK, CARLOS F. M.. NA damage and oxidative stress in human cells infected by Trypanosoma cruz. PLOS PATHOGENS, v. 17, n. 4, . (13/08028-1, 17/01760-0, 19/19435-3)
SATO, JULIANA L.; FONSECA, MARINA R. B.; CERDEIRA, LOUISE T.; TOGNIM, MARIA C. B.; SINCERO, THAIS C. M.; NORONHA DO AMARAL, MARIO C.; LINCOPAN, NILTON; GALHARDO, RODRIGO S.. Genomic Analysis of SXT/R391 Integrative Conjugative Elements From Proteus mirabilis Isolated in Brazil. FRONTIERS IN MICROBIOLOGY, v. 11, . (19/19435-3, 15/11348-3, 18/23872-7)
REILY ROCHA, CLARISSA RIBEIRO; ROCHA, ALEXANDRE REILY; SILVA, MATHEUS MOLINA; GOMES, LUCIANA RODRIGUES; LATANCIA, MARCELA TEATIN; TOMAZ, MARINA ANDRADE; DE SOUZA, IZADORA; SEREGNI MONTEIRO, LINDA KAROLYNNE; MARTINS MENCK, CARLOS FREDERICO. Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries. CELLS, v. 9, n. 12, . (13/08028-1, 19/19435-3, 19/21745-0, 15/25016-2)
WATANABE, INGRID KAZUE MIZUNO; ANDRADE-SILVA, MAGAIVER; FORESTO-NETO, ORESTES; FELIZARDO, RAPHAEL JOSE FERREIRA; MATHEUS, MARCO AURELIO COSTA; SILVA, REINALDO CORREA; CENEDEZE, MARCOS ANTONIO; HONDA, TAMISA SEEKO BANDEIRA; PERANDINI, LUIZ AUGUSTO BUORO; VOLPINI, RILDO APARECIDO; et al. Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice. FRONTIERS IN IMMUNOLOGY, v. 11, . (14/50833-1, 17/05264-7, 19/19435-3)
FUENTES-LEON, FABIANA; DE OLIVEIRA, ANDRESSA PERES; QUINTERO-RUIZ, NATHALIA; MUNFORD, VERIDIANA; KAJITANI, GUSTAVO SATORU; BRUM, ANTONIO COIMBRA; SCHUCH, ANDRE PASSAGLIA; COLEPICOLO, PIO; SANCHEZ-LAMAR, ANGEL; MARTINS MENCK, CARLOS FREDERICO. DNA Damage Induced by Late Spring Sunlight in Antarctica. Photochemistry and Photobiology, v. 96, n. 6, . (19/19435-3)
QUINTERO-RUIZ, NATHALIA; CORRADI, CAMILA; MORENO, NATALIA CESTARI; DE SOUZA, TIAGO ANTONIO; PEREIRA CASTRO, LIGIA; ROCHA, CLARISSA RIBEIRO REILY; MENCK, CARLOS FREDERICO MARTINS. Mutagenicity Profile Induced by UVB Light in Human Xeroderma Pigmentosum Group C Cells(dagger). Photochemistry and Photobiology, . (13/08028-1, 19/19435-3)
MONTEIRO DE ASSIS, LEONARDO VINICIUS; MENDES, DAVI; SILVA, MATHEUS MOLINA; KINKER, GABRIELA SARTI; PEREIRA-LIMA, ISABELLA; MORAES, MARIA NATHALIA; MARTINS MENCK, CARLOS FREDERICO; DE LAURO CASTRUCCI, ANA MARIA. Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 10, . (14/27287-0, 19/19435-3, 13/24337-4, 17/24615-5, 12/50214-4, 18/16511-8, 17/26651-9, 17/18781-0, 18/14728-0, 17/24217-0)
KAJITANI, GUSTAVO SATORU; BRACE, LEAR; TREVINO-VILLARREAL, JOSE HUMBERTO; TROCHA, KASPAR; MACARTHUR, MICHAEL ROBERT; VOSE, SARAH; VARGAS, DORATHY; BRONSON, RODERICK; MITCHELL, SARAH JAYNE; MARTINS MENCK, CARLOS FREDERICO; et al. Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model. AGING-US, v. 13, n. 19, p. 22710-22731, . (19/19435-3, 13/08028-1)
DE ASSIS, LEONARDO VINICIUS MONTEIRO; MORAES, MARIA NATHALIA; MENDES, DAVI; SILVA, MATHEUS MOLINA; MENCK, CARLOS FREDERICO MARTINS; CASTRUCCI, ANA MARIA DE LAURO. Loss of Melanopsin (OPN4) Leads to a Faster Cell Cycle Progression and Growth in Murine Melanocytes. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 43, n. 3, p. 1436-1450, . (18/16511-8, 17/24615-5, 17/26651-9, 17/18781-0, 19/19435-3, 18/14728-0, 17/24217-0)

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