Keeping time: circadian clock responses to environmental challenge

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Introduction. This PhD project examines how our internal clocks translate external timing (such as the light and dark environment) into complex physiological rhythms. It will specifically address the impact of clock disruption on mammalian physiology, and test whether pharmacological targeting of the clockwork may counteract environmental or pathological clock disruption. These studies closely align to the BBSRC's strategic initiatives on understanding biological rhythms and lifetime of health and build on a long-standing and successful collaboration between the University of Manchester and Pfizer.Background. Daily 24-hour rhythms are present in virtually all aspects of our behaviour and physiology, ranging from our sleep-wake cycle, to fluctuations in body temperature, blood pressure and circulating hormones. These rhythms are driven by internal timing systems (circadian clocks) that run throughout the body, and act within each tissue to orchestrate organ function and rhythmic activity. In mammals, circadian timing is headed by a 'master clock' located in a small area of thebrain called the suprachiasmatic nucleus (SCN). Importantly, the SCN synchronises clocks in the rest of the brain and body, so that the activities of different organ systems are coordinated with each other, as well as with overriding behavioural cycles (i.e. when we eat, when we sleep, etc.). The SCN also keeps in time with the environment through direct relays of photic information from the retina. Understanding how the circadian system works, and how it directs diverse physiological pathways cross the body has become increasingly important because we now recognize that disruption of our clocks is commonly observed with many pathological conditions. For example, lifestyles that disturb these clocks, such as shift-work, increase the incidence of diseases including cancer and diabetes. Circadian disruption is also recognized as an important feature of many neurological disorders in including dementia and bipolar depression.Methodology. This PhD proposal will examine how internal timers align our physiology to the environment and what the consequences are when that alignment is disrupted. Importantly these studies will detail circadian clock function at both a molecular and physiological level. At a molecular level we will use clock-gene reporter systems and longitudinal measures of gene/protein expression to detail how the molecular clockwork in different tissues responds to changes in environmentalinputs (such as light or temperature). These studies will be paralleled by comprehensive measures of behavioural and physiological rhythms (e.g. locomotor activity, thermogenesis, feeding behaviour, metabolic rate), using models of environmental challenge (e.g. repeated shift of the light/dark cycle; akin to chronic shift work) and genetic models of inappropriate entrainment (e.g. CK1etau and Aft mutant mice; which model human familial advanced sleep phase and delayed sleep phase). This will also allow us to test how clock re-setting stimuli and drugs (e.g. CK1e antagonists) impact on a broad-spectrum of physiological rhythms. These studies will benefit from an exciting new method to track oscillations in gene activity in free-moving mice. This is achieved by injecting a virus containing a light-emitting gene, which oscillates in response to activation of a specific clock-driven or metabolic pathway. Thus, we can track how the core clockwork of a given tissue responds to altered environment and/or to pharmacological targeting.