Projects / Programmes
Impact of oxidative stress on length and structure of telomeres in children and adolescents with type 1 diabetes or hypercholesterolemia
| Code |
Science |
Field |
Subfield |
| 3.05.00 |
Medical sciences |
Human reproduction |
|
| Code |
Science |
Field |
| B660 |
Biomedical sciences |
Pediatrics |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Telomere length, type 1 diabetes, hypercholesterolemia, oxidative stress, G-quadruplexes
Researchers (25)
Organisations (2)
Abstract
Telomeres are DNA-protein complexes capping the end of eukaryotic chromosomes. Their role is to ensure genomic stability and prevent chromosomal breaks ultimately leading to apoptosis. Consequently, length, dynamics and structure of telomeres are extensively investigated in aging, cancer and complex disorders but their role is still not completely explained. Telomeres are considered to be an important biomarker, combining the effect of various factors, such as the total number of cell divisions and the cumulative exposure of cells to the oxidative and nitrosative stress. Telomere length (TL) is inversely correlated with oxidative stress, since the combination of prolonged exposure to reactive oxidative species (ROS) leads to increased rate of telomere ends deterioration. Telomeres and oxidative stress are believed to play an important role in aetiology of complex chronic disorders like diabetes, atherosclerosis (ATS), cardiovascular disease (CVD) and their complications.
The effect of oxidative/nitrosative stress on telomere dynamics is an important field of research. Even more, when the studied disorders are type 1 diabetes (T1D) and hypercholesterolemia (HCH) representing the major morbidity and mortality contributors in developed world. The dynamics of telomeres in a group of children and adolescents with T1D and HCH will be the main focus of our project. Participants with T1D will be grouped according to the manifestation of T1D complications. Participants with HCH will be additionally sub-grouped according to the genetic background of the disease and statin treatment. Studies on TL in paediatric populations are limited. There are far less accompanying diseases present in the paediatric population enabling clearer interpretation of results and identification of basic disease aetiology compared to the adult population. Our aim is to evaluate TL in correlation with 1) clinical data of participants, 2) oxidative stress biomarkers and 3) genetic predisposition for oxidative stress and telomere stability management. Identification of additional biomarkers of oxidative and nitrosative stress (i.e. 8-hydroxy-2-deoxy-guanosine, 3-nitro-tyrosine) will enable us to determine physiological conditions of telomere shortening in a group of chronically ill children. Results of this part of the project will be the basis for in vitro structural studies researching influence of reactive species on the telomere structure.
The newly obtained data will enable us to identify patients with potentially higher risk for developing early chronic complications of T1D and HCH. Identification of these patients in pre-clinical stage will enable us to design specific preventive strategies and thus significantly decrease the early morbidity and mortality of these devastating conditions. Proposed project is based upon multidisciplinary methodology, believed to be a cornerstone in development of personalized medicine approaches in the disease management. Understanding the oxidative stress influence on telomere dynamics, length and structure will significantly improve basic knowledge on the field.
Significance for science
Proposed project was based upon multidisciplinary methodology, believed to be a cornerstone in development of individualized management of disease. Understanding the oxidative stress influence on telomere length, telomere attrition dynamics and telomere structure had significantly improved basic knowledge on the field. We proved that poor management of type 1 diabetes translates relatively quickly after the disease onset into the accelerated rate of telomere attrition, potentially mediated by an excessive amount of nitrogen reactive species. The lost telomere length most likely cannot be redeemed and may potentially lead to type 1 diabetes complications. Additionally, shorter telomere length were related to increased risk for development of atherosclerosis and cardiovascular complications in children with hypercholesterolemia as soon as in preclinical phase of the disease, since aorta stiffness was only implied. Patients with causative mutation for familial hypercholesterolemia did not have shorter telomeres compared to the patients with polygenic hypercholesterolemia. This implies that elevated levels of cholesterol have greater impact on the telomere attrition than the genetic cause for this elevation. Evaluation of this knowledge together with clinical characteristics, oxidative stress biomarkers and genetic predisposition for oxidative stress management will bring important new basic knowledge on aetiology of complications in both disorders as well as provide further new clinically relevant knowledge. Studies on this carefully selected and clinically well determined cohort of patient had contributed to prediction of the disease progression and development of disease complications. This has an important role in clinical management of the disease.
Significance for the country
The study had supplemented basic knowledge and clinically relevant new knowledge. These results contribute to the possibility of risk determination and early identification of individuals at higher risk for development of type 1 diabetes and hipercholesterolemia complications, such as arthrosclerosis and cardiovascular diseases. Those together are the leading cause of morbidity in developed world. Therefore, early prevention of complications and late sequel with design of specific preventive strategies would be possible and with it significant decrease in the early morbidity and mortality of these conditions. In long term, the results may indirectly improve the medical service provided to patients with hypercholesterolemia and type 1 diabetes, and further development of early and/or individualised treatment and possible prevention of disease complications. With this, increase of the quality of life of patients and their families would be possible, decrease of the amount of working days lost by the caregivers and adult patients and decrease of direct and indirect costs related to this pathology.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
