Matthew P. Butler - US grants

Abstract One in four deaths in the United States is caused by cardiovascular disease?an enormous public health burden. An under-appreciated risk factor for heart disease is obstructive sleep apnea (OSA). In OSA, the upper airway collapses repeatedly during sleep and prevents breathing. We have found that the duration of these respiratory events is heritable and is a risk factor for heart disease and death. We believe that the time course of breathing disturbances through the night is a rich source of information about a patient's OSA severity and the patient's long term risk for heart disease. OSA severity is currently defined by the mean number of respiratory events per hour asleep (apnea-hypopnea index, AHI). This number ignores physiologically significant variation in event duration, their spacing, and association with different sleep stages. Moreover, current clinical cutoffs for mild, moderate, and severe OSA are not based on any physiological mechanism. We have therefore analyzed two physiologically informative parameters?the duration of respiratory events and their clustering within the night?and have found that those with short and regularly occurring respiratory events are at the greatest risk of dying. Event duration is the most heritable of OSA traits, suggesting a potential genetic underpinning to this phenotype. Our goals in this project are to determine how respiratory event duration and inter-event variability predict future cardiovascular disease using prospective data sets available through the National Sleep Research Resource. We will test whether these novel OSA metrics predict risk in multiple independent cohorts to establish their generalizability, and we will determine whether these metrics help stratify differential risk between men and women. To date, the AHI has not been shown to be a good predictor of future risk in women, yet therapeutic management for women continues to be guided by this single number. Identifying better predictors for women from the information contained in the night-time polysomnogram has the potential to dramatically change the therapeutic strategies for women with OSA. Finally, in cross-sectional studies, we will test whether subjects with short regularly occurring respiratory events have elevated markers of cardiovascular risk, based on state-of-the-art imaging measures of cardiac function and coronary artery calcification.

Abstract Time of day is a strong determinant of our experience: waking, sleeping, meals, and working occur in predictable patterns. Endogenous clocks in the brain and peripheral tissues control the appropriate timing of physiology and behavior. But people are not all synchronized in the same way?some have an early chronotype (larks) and some have a late chronotype (owls). As with more severe disruptions of the clock, delayed chronotype is a predictor of sleep disorders, metabolic disease, and neurological disorders. Importantly, chronotype also differs between sexes, so differences in biological clock function may explain some of the sex biases in these pathologies. We have previously shown that (1) circadian clock function is strongly influenced by steroid hormones in males but not in females, (2) this is due to a change in the sensitivity of the clock to light, and (3) this is traceable to the effects of androgens on light-responsive neurons that express androgen receptors (AR) in the suprachiasmatic nucleus?the location of the brain?s circadian clock. Though lacking AR, the same neuronal population exists in females. The circadian clock is therefore an excellent system to determine the structural and functional pathways by which biological sex and androgen signaling control a circadian clock function (free-running period of the clock) and an output behavior (chronotype) that have relevance for health. We hypothesize that androgens reduce the clock?s photosensitivity to compensate for underlying organizational differences and thereby ensure similar behavior patterns between males and females. We will first investigate how androgens affect the excitability of identified AR-expressing neurons (Aim 1) and how this alters the spatiotemporal network of the brain?s clock (Aim 2). Next, we test how the presence of the receptor affects rhythmic behavior and light sensitivity (Aim 3). Finally, we will pharmacogenetically manipulate AR neurons for the first time in any neuronal system to determine the role that these neurons play in organizing clock function and controlling its response to light (Aim 4). These Aims are enabled by two important mouse models: one in which the AR can be knocked out conditionally, and one in which AR neurons express CRE recombinase. Using the latter, SCN neurons expressing AR can be identified and manipulated by pharmacogenetics.