DESCRIPTION (provided by applicant): Salicylic acid (SA) is the oldest herbal medicine known to mankind. In recent years, long-term use of "baby" aspirin (acetylated SA) has been shown to prevent cardiovascular diseases and significantly reduce deaths from certain types of cancer (e.g., colon cancer). Non-acetylated SA derivatives have shown promising results in treating type II diabetes in clinical trials. However, how this small phenolic compound can have such diverse medicinal effects is not completely understood. SA is naturally a plant immune signal induced upon pathogen challenge. Local increase in SA is associated with programmed cell death (PCD) of infected cells and effector- triggered immunity (ETI). Subsequently, SA synthesis is induced in systemic (non-infected) tissue through an unknown mechanism to promote cell survival and confer broad-spectrum systemic acquired resistance (SAR). Studies showed that SA binds and inhibit several ROS scavenging enzymes and controls the nuclear translocation of the master immune regulator NPR1 through changes in cellular redox. In the nucleus, NPR1 serves as a transcription cofactor for multiple transcription factors involved in PCD/ETI- or SAR-related gene expression. Recent studies in Arabidopsis showed that in the absence of pathogen challenge, the basal SA level oscillates in a circadian manner and is controlled by the redox sensitive circadian clock component, CHE. This clock component is also required for pathogen-induced SA synthesis in systemic tissue during SAR, suggesting the involvement of redox and the circadian clock in transmitting the immune signal. Moreover, NPR1 has been found to regulate transcription of not only immune-related genes, but also the morning (LHY, PRR7) as well as the evening (TOC1) components of the central circadian clock indicating that this immune regulator is also an intrinsic regulator of the clock. The main question that will be addressed by this project is how the circadian clock and the metabolic rhythms integrate cues, such as SA, to time and synchronize energy-intensive physiological processes such as growth and defense in a manner that is beneficial to the whole organism. This project will train the next generation of scientists and make discoveries that may lead to better understanding of the profound effects that SA has in plants and in humans at the molecular and systems level.