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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 Investigator:Carlos Frederico Martins Menck
Grantee:Carlos Frederico Martins Menck
Principal investigator abroad: Erik Biessen
Institution abroad: Maastricht University, Maastricht (UM), Netherlands
Principal investigator abroad: Ingrid van der Pluijm
Institution abroad: Erasmus University Rotterdam (EUR), Netherlands
Principal investigator 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
Co-Principal Investigators: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):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
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

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)

Articles published in other media outlets (6 total):
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Plantão News (MT): Estudo na Antártica confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (23/Feb/2021)
Espaço Ecológico no Ar: Estudo confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (23/Feb/2021)
Cosmetic Innovation: Estudo na Antártica confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (23/Feb/2021)
Consecti - Conselho Nacional de Secretários Estaduais para Assuntos de CT&I: Estudo na Antártica confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (22/Feb/2021)
Revista Amazônia: Estudo na Antártica confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (22/Feb/2021)
Planeta online: Estudo confirma: quanto mais fina a camada de ozônio, maior é o dano do sol na pele (22/Feb/2021)

Scientific publications (8)
(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)
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; PACHECO-SILVA, ALVARO; CAMARA, NIELS OLSEN SARAIVA. Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice. FRONTIERS IN IMMUNOLOGY, v. 11, DEC 22 2020. Web of Science Citations: 0.
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; FOTORAN, WESLEY; TORRES, JANAINA IANNICELLI; DE ANDRADE, JAILSON BITTENCOURT; VERAS, MARIANA MATERA; ARTAXO, PAULO; MARTINS MENCK, CARLOS FREDERICO; VASCONCELLOS, PEROLA DE CASTRO; SALDIVA, PAULO. 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, DEC 2020. Web of Science Citations: 0.
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 DEC 2020. Web of Science Citations: 0.
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, OCT 20 2020. Web of Science Citations: 0.
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 OCT 2020. Web of Science Citations: 0.
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 SEP 2020. Web of Science Citations: 0.
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 JUL 2020. Web of Science Citations: 1.
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 JUN 2020. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.