Circadian and daily rhythms regulate many aspects of physiology and behavior. Although a growing number of studies suggest that circadian disruptions may render organisms more susceptible to infection and cancer, the molecular links between the circadian system and the immune system are largely unknown. Natural killer (NK) cell cytolytic activity has been shown to follow a daily rhythm, which is under a circadian control. NK cells participate in the immune response against viral infections and cancer. Employing the rat animal model, this proposal determines the mechanisms by which the circadian rhythm of splenic NK cell cytolytic function is regulated. It tests the hypothesis that splenic NK cells are provided with molecular clocks that orchestrate the rhythmic expression of cytolytic factors that drive the circadian rhythm of NK cell cytolytic function. The hypothalamic suprachaismatic nucleus, which is itsetf, entrained by photic input, coordinates the expression of clock regulatory genes by altering the sympathetic outflow to the splenic NK cells. The proposed research uses magnetic separation techniques to isolate the NK cell population from the spleen to determine the changes in cytotoxic factors, cytokines and clock genes in these cells;employs gene knockdown techniques in NK cells to study the influence Of clock genes on cytolytic function;analyzes the circadian variations in the clearance of NK-sensitive tumor cells;determines the susceptibility of NK cell function to jet lag, a common circadian disruption, and uses pharmacological tools to investigate the signaling mechanism critically involved in resetting the circadian clock in splenic and clonal NK cells. The proposed series of studies should enhance our knowledge of the physiological mechanisms orchestrating NK cell circadian function.
In the last few years, the medical practice of timed administration of drugs based on biological rhythms has been extensively developed, especially in immune-related diseases, heart disease and in cancer therapy. Identifying the mechanisms that orchestrate the circadian rhythm of NK cell function could lead to better designed chronomodulated treatments for cancer, HIV, and other immune-related diseases.
| Cermakian, Nicolas; Lange, Tanja; Golombek, Diego et al. (2013) Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 30:870-88 |
| Logan, Ryan W; Zhang, Changqing; Murugan, Sengottuvelan et al. (2012) Chronic shift-lag alters the circadian clock of NK cells and promotes lung cancer growth in rats. J Immunol 188:2583-91 |
| Logan, Ryan W; Sarkar, Dipak K (2012) Circadian nature of immune function. Mol Cell Endocrinol 349:82-90 |
| Logan, Ryan W; Arjona, Alvaro; Sarkar, Dipak K (2011) Role of sympathetic nervous system in the entrainment of circadian natural-killer cell function. Brain Behav Immun 25:101-9 |
