The intrinsic circadian clock regulates a wide variety of processes, including an organism’s response to anticancer genotoxic treatments and immune response. The major goal of my research program is to understand how various stress response pathways cross-talk with the circadian clock and how these pathways can be modulated by the activity of core circadian proteins. For this, we use a variety of cellular and mouse models deficient in various components of the molecular clock. This approach allowed us to identify a previously unknown mechanistic link between the key regulator of immune response NF-kB and core circadian protein CLOCK, which in addition to its bona fide circadian function, directly modulates the activity of p65.
Another research direction of my laboratory is focused on understanding the basic mechanisms of aging, the role of the circadian system in this process and testing potential anti-aging compounds in various models of chronological and premature aging. Overall, our program presents a broad approach to study the role of the circadian system in many biological processes both under normal and stress conditions. It may eventually result in the development of novel therapeutic strategies that will modulate various biological responses through the components of the molecular clock.
Current and former support was provided by National Institute of Health, Alliance Foundation and Everon, Inc.
Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, Antoch MP. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc Natl Acad Sci USA 102 (9):3407-3412, 2005. PMCID: PMC546637
Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20(14):1868-1873, 2006. PMCID: PMC1522083
Antoch MP, Chernov MV. Pharmacological modulators of the circadian clock as potential therapeutic drugs. Mut Res. 2009; 17-23
Hu Y, Spengler ML, Kuropatwinski KK, Comas-Soberats M, Jackson M, Chernov MV, Gleiberman AS, Fedtsova N, Rustum YM, Gudkov AV, Antoch MP. Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1. Oncotarget. 2011 Dec;2(12):1279-90. PMID:22249125
Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, Gitlin II, Artemicheva NM, Deluca KA, Gudkov AV, Antoch MP. Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated transcription. Proc Natl Acad Sci U S A. 2012 Sep 11; 109 (37):E2457-65. doi: 10.1073/pnas.1206274109. Epub 2012 Aug 15.
Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, Gudkov AV, Antoch MP. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis. Aging (Albany NY). 2012 Oct;4(10):715-22. PMID:23117593
Comas M, Kuropatwinski KK, Wrobel M, Toshkov I, Antoch MP. Functional clock is retained both in spontaneously developed sarcomas and in xenografts grown in immunocompromized SCID mice. Chronobiol Int. 2014 Jun 16:1-10.