Center for Gene Regulation in Health and Disease (GRHD)

Roman Kondratov

Biological clocks regulate organism physiology and behavior. The circadian clocks are one class of such clocks, which generate 24 hr rhythms in order to adapt to 24-hour light/dark cycle. It was known for years that the circadian system controls many behavioral processes such as daily locomotor activity and sleep/wake cycle. What was emerging over last years is that the circadian clock is key regulator of metabolism, cardiovascular physiology, immune and stress response systems.Our laboratory was instrumental in establishing a connection between the circadian clock and aging.


We have reported that knockout of the key circadian protein BMAL1 results in syndrome of early aging in mice - the significantly reduced life span (9 months for knockout vs. 28 months for wild type animals) and the development of multiple age-related pathologies (such as sarcopenia, osteoporosis, reduction of subcutaneous adipose tissue, decreased hair growth, cataracts, cornea inflammation, etc.).

Being a transcriptional factor, BMAL1 may orchestrate or influence many metabolic pathways in the organism. Therefore, different mechanisms may be responsible for aging and for the development of particular pathologies in BMAL1 deficient animals. Currently we have several projects related to the study the role of BMAL1 and circadian clock in the regulation of aging. One direction is study of aging associated signaling pathways such as TOR signaling pathways, Sirtuin signaling pathway and insulin-like growth factor/insulin-like growth factor receptor (IGF/IGFR) pathway. All these pathways play important role in cell metabolism and proliferation and organism response to nutrients and stress. These pathways are tightly regulated and disruption of the regulation is the major determinant of aging and age-related pathologies.

Another interest of the laboratory is circadian clock dependent mechanisms of dietary restriction. Dietary restriction and calorie restriction particularly is one of the most powerful interventions, which extend longevity in different organisms including mammals. We found that calorie restriction significantly affect circadian rhythms in gene expression and that functional circadian clock is necessary for lifespan extension by calorie restriction.
    
Stem cell homeostasis is implicated in the control of aging. We are concentrated on circadian clock mechanisms in mesenchymal stem cells and, specifically, on the role of clock proteins in osteoblast differentiation. This research will help to establish involvement of the circadian clock in such age associated pathology as osteoporosis. 

  • Sonal Patel
    PhD Student
    Location: 
    SR271
  • William Samsa
    PhD Student
    Location: 
    SR271
  • Nikkhil Velingkaar
    Ph student
    Location: 
    SR271
    216-523-7199
  • Yuliya Dubrovsky
    Alumni. Research Technician 2007-2013, Current position Occupational Therapist
    Location: 
    SR271
  • Rohini Khapre
    Alumni, PhD Student 2009 - 2014, Currently postdoc fellow at Cleveland Clinic
    Location: 
    SR271

Selected publications (in chronological order)  

1. Komarov P.G., Komarova E.A., Kondratov R.V., Christov-Tselkov K., Coon J.S., Chernov M.V., Gudkov A.V.(1999) A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science, Sep 10, 285, 1733-37

2. Kondratov R.V., Komarov P.G., Becker Y., Ewenson A., Gudkov A.V. (2001) Proceedings of The National Academy of Sciences of U.S.A., 98(24), 14078-14083

3. Kondratov R.V., Chernov M.V., Kondratova A.A., Gorbacheva V., Gudkov A.V., and Antoch M.P. BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. (2003) Genes and Development, August , 17(15), 1921-1932

4. Komarova, E.A., Kondratov R.V., Wang K., Christov K., Golovkina T.V., Goldblum J.R., and Gudkov A.V. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastrointestinal syndrome in mice  (2004) Oncogene, 23(19), 3265-71.

5. Singhi A., Kondratov R.V., Chernov M.V., and Gudkov A.V.  Selection-subtraction approach (SSA): universal genetic screening technique that enables negative selection. (2004) Proceedings of The National Academy of Sciences of U.S.A., 101(25), 9327-32

6. Gorbacheva V.Y., Kondratov R.V., Zhang R., Gudkov A.V., Takahashi J.S., and Antoch M.P. (2005) Circadian control of drug response: mouse sensitivity to chemotherapeutic drug cyclophosphamide is modulated by the functional status of CLOCK/BMAL1 transactivation complex.  Proceedings of The National Academy of Sciences of U.S.A., 102(9), 3407-3412

7. Kondratov R.V*., Kondratova A.A., Lee C., Gorbacheva V.Y., Chernov M.V., and Antoch M.P. Posttranslational regulation of circadian CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. (2006), Cell Cycle, 5(8), 890-895

8. Kondratov R.V*., Kanagal R., Kondratova A.A., Gorbacheva V. Y., and Antoch M. P. Dual role of CLOCK/BMAL1 circadian complex in the transcription control. (2006) FASEB J.,  20(3), 530-532

9. Kondratov R.V*., Kondratova A.A., Gorbacheva V.Y., Vykhovanets O.V. and Antoch M.P.  Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. (2006) Genes and Development, 20(14), 1868-1873

10. Kondratov R.V. A role of the circadian system and circadian proteins in aging. (2007) Ageing Research Review, 6(1), 12-27

11. Kondratov R.V. and Antoch M.P. Circadian proteins in the regulation of cell cycle and genotoxic stress responses. (2007), Trends in Cell Biology, 17(7), 311-317

12. Kondratov R.V,* Vykhovanets O, Kondratova AA, Antoch MP. (2009)  Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging (Albany NY). 1(12):979-87.

13. Antoch MP and Kondratov R.V. (2010)  Circadian proteins and genotoxic stress response. Circ Res. 106(1):68-78. Review.

14. Kondratova A.A.,Dubrovsky Yu., Antoch M.P. & Kondratov R.V. (2010) Circadian clock controls adaptation to novel environment and memory formation. Aging (Albany NY).  2(5), 285-297

15. Khapre R., Samsa W., & Kondratov R.V. (2010) Circadian regulation of cell cycle: molecular connection between circadian clock and aging. Annals of Medicine. 42(6), 404-415
35. Dubrovsky Yu. Samsa W., & Kondratov R.V. (2010) Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging (Albany NY).  2(12), 936-944

16. Khapre R.V., Kondratova A.A., Susova O.S., & Kondratov R.V. (2011) Circadian clock protein BMAL1 regulates cellular senescence in vivo. Cell Cycle 10(23), 4162-4169

17. Jeyaraj D., Haldar S.M., Wan X., McCauley M.D, Ripperger J.A., Hu K., Lu Y., Eapen B.L., Sharma N., Ficker E., Cutler M.J., Gulick J., Sanbe A., Robbins J., Demolombe S., Kondratov R.V., Shea S.A., Albrecht U., Wehrens X.H.T., Rosenbaum D.S. and Jain M.K. (2012) Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature, 483, 96-99

18. Kondratova A.A. & Kondratov R.V. (2012) Circadian clock and pathologies of ageing brain. Nature Reviews Neuroscience 13, 325-335

19. Kondratov R.V. (2012) Cell-autonomous circadian DNA damage response: is the case closed? Cell cycle, 11(20)

* - co-correspondence author.