Circadian oscillations of physiological functions and immune response to infectious agents are two major adaptive control mechanisms involving transcriptional modulation of numerous genes causing multiple and significant physiological effects. Our preliminary data reveal existence of a bi-directional interaction between the circadian regulatory mechanism and responsiveness of an organism to immune challenge mediated via Toll-like receptors. Importantly, we identified major players of the cross- talk connecting the circadian and immune response by demonstrating a physical and functional interaction between the core circadian transcription factors CLOCK and BMAL1 and the major mediator of immune response NFkB. Our preliminary studies support the hypothesis that the circadian histone acetyltransferase activity of CLOCK is a co-activator of NFkB-dependent gene expression, and that NFkB, in turn, directly mediates repression of CLOCK/BMAL1-dependent transcription presumably through posttranslational mechanisms. The proposed program is focused on detailed mechanistic and physiological characterization of the CLOCK/NFkB cross-talk in mouse models and its role in determining inflammatory responses, circadian functions and response to systemic genotoxic stresses known to be influenced by both pathways. The completion of the proposed program will result in defining "regulatory rules" and molecular mechanisms involved in the cross-talk between two most fundamental systems controlling the organismal interaction with its environment. It will lay the ground for new approaches and reagents for rational pharmacological modulation of inflammation and circadian functions with potential impact to treat or prevent a variety of pathologies.

Public Health Relevance

Almost all physiological processes in our body are controlled by internal biological clocks. Importantly, biological clocks can modulate regulation of components of the immune system. Our proposed research is directed to understanding of how biological clocks and immune system interact at molecular level. We believe that this knowledge will help to discover new approaches for modulation of inflammation with potential impact to treatment or prevention of a variety of pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095874-04
Application #
8685278
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Sesma, Michael A
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
$361,486
Indirect Cost
$161,671
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Casey, Theresa M; Crodian, Jennifer; Erickson, Emily et al. (2014) Tissue-specific changes in molecular clocks during the transition from pregnancy to lactation in mice. Biol Reprod 90:127
Comas, Maria; Kuropatwinski, Karen K; Wrobel, Michelle et al. (2014) Daily rhythms are retained both in spontaneously developed sarcomas and in xenografts grown in immunocompromised SCID mice. Chronobiol Int 31:901-10
Antoch, Marina P; Kondratov, Roman V (2013) Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy. Handb Exp Pharmacol :289-309