Understanding 3-methyladenine DNA glycosylase-mediated cell death in response to m...
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)