STOCHASTIC SIMULATION MODELING OF CELL TELOMERE SHORTENING MECHANISMS IN AGEING AND DISTURBANCE DEVELOPMENT PROCESSES
Abstract
Some issues of applying the stochastic simulation modeling to the description and stud ying of DNA’s end structures (telomeres) shortening mechanisms are considered. The aim of this research is to study — on the base of the st ochastic and simulation modeling — processes in the cells leading to the telomeres’ length shortening, and as a co nse quence, to decreasing the proliferative capacity, and developing pathologies including oncologic one s. The mat hematical model is described in the semimartingale terms. The analysis of the modeling results is bas ed on their comparison to the biological expe riments data. The formed cell distribution in accordance to their telomeres’ length is compared with the e x perimental data obtained through the tests performed with human fibroblast - culture using Levy — Prokhorov metric. The study results can be used in bi omedical research on ageing, and on developing var ious pathologies, as well as in solving a number of problems in the field of gero n tology.
Keywords
stochastic simulation modeling,
semimartingale,
compensator,
DNA,
telomere,
telomerase,
aging,
ca rcinogene sis,
oxidative stress,
free radicals.
Supporting agencies: Ministry of Education and Science of the Russian Federation
About the Authors
Alexander Alexandrovich Butov
Ulyanovsk State University, Russia
Russian Federation
Russian Federation
Mikhail Andreyevich Karev
Ulyanovsk State University, Russia
Russian Federation
Russian Federation
Sergey Alexandrovich Khrustalev
Ulyanovsk State University, Russia
Russian Federation
Russian Federation
References
1. Blackburn, E.-H. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions / E.-H. Blackburn // FEBS Letters. — 2005. — Vol. 579. — Pp. 859‒862.
2. Blasco, M.-A. Telomere length, stem cells and aging / M.-A. Blasco // Nature Chemical Biology. — 2007. — Vol. 3. — Pp. 640‒649.
3. Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease / H. Jiang [et al.] // Proceedings of the National Academy of Sciences of the United States of America. — 2008. — Vol. 105. — Pp. 11299‒11304.
4. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells / R.-T. Calado [et al.] // Blood. — 2009. — Vol. 114. — Pp. 2236‒2243.
5. Calado, R.-T. Telomere Diseases / R.-T. Calado, N.-S. Young // The New England Journal of Medicine. — 2009. — Vol. 361. — P. 2353‒2365.
6. Proctor, C.-J. Modelling telomere shortening and the role of oxidative stress / C.-J. Proctor, T.-B.-L. Kirkwood // Mechanisms of Ageing and Development. — 2002. — Vol. 123. — Pp. 351‒363.
7. Sozou, P.-D. A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA / P.-D. Sozou, T.-B.-L. Kirkwood // Journal of Theoretical Biology. — 2001. — Vol. 213. — Pp. 573‒586.
8. Rubelj, I. Stochastic mechanism of cellular aging — abrupt telomere shortening as a model for stochastic nature of cellular aging / I. Rubelj, Z. Vondracek // Journal of Theoretical Biology. — 1999. — Vol. 197. — Pp. 425‒438.
9. Wein, L.-M. Estimation of replicative senescence via a population dynamics model of cells in culture / L.-M. Wein, J.-T. Wu // Experimental Gerontology. — 2001. — Vol. 36. — Pp. 79‒88.
10. Arino, O. Mathematical modeling of the loss of telomere sequences / O. Arino, M. Kimmel, G.-F. Webb // Journal of Theoretical Biology. — 1995. — Vol. 177. — Pp. 45‒57.
11. Tan, Z. Simulated shortening of proliferation-restricting telomeres during clonal proliferation and senescence of human cells / Z. Tan // Experimental Gerontology. — 2001. — Vol. 36. — Pp. 89‒97.
12. Zglinicki, T. Stress, DNA damage and ageing — an integrative approach / T. Zglinicki, A. Burkle, T.-B.-L. Kirkwood // Experimental Gerontology. — 2001. — Vol. 36. — Pp. 1049‒1062.
13. Blagoev, K. B. Telomere exchange and asymmetric segregation of chromosomes can account for the unlimited proliferative potential of ALT cell populations / K. B. Blagoev, E. H. Goodwin // DNA Repair. — 2008. — Vol. 7. — Pp. 199‒204.
14. Qi, Q. Mathematical modelling of telomere Dynamics / Q. Qi // Thesis submitted to The University of Nottingham for the degree of Doctor of Philosophy. — Nottingham, 2011. — 210 p.
15. Grasman, J. Stochastic modelling of length dependent telomere shortening in Corvus monedula / J. Grasman, H.-M. Salomons, S. Verhulst // Journal of Theoretical Biology. — 2011. — Vol. 282. — Pp. 1‒6.
16. Kapitanov, G. A. Mathematical Model of Cancer Stem Cell Lineage Population Dynamics with Mutation Accumulation and Telomere Length Hierarchies / G. A. Kapitanov // Mathematical Modelling of Natural Phenomena. — 2012. — Vol. 7. — Pp. 136‒165.
17. Tchirkov, A. Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-elangiectasia / A. Tchirkov, P. M. Lansdorp // Human Molecular Genetics. — 2003. — Vol. 12. — Pp. 227‒232.
18. Accumulation of short telomeres in human fibroblasts prior to replicative senescence / U.-M. Martens [et al.] // Experimental Cell Research. — 2000. — Vol. 256. — Pp. 291‒299.
Review
For citations:
Butov A.A., Karev M.A., Khrustalev S.A. STOCHASTIC SIMULATION MODELING OF CELL TELOMERE SHORTENING MECHANISMS IN AGEING AND DISTURBANCE DEVELOPMENT PROCESSES. Vestnik of Don State Technical University. 2014;14(1):98-109. (In Russ.) https://doi.org/10.12737/3509
Views:
483
Email this article 