Eve Van Cauter, PhD - US grants

In normal man, plasma glucose responses to oral glucose, meals or intravenous glucose may be more than 100% larger in the evening than in the morning. These morning-evening differences are related to a diurnal variation in set-point of the glucose regulation with maximal glucose levels around midsleep. This diurnal variation persists during continuous bedrest, is independent of the feeding schedule and is not directly related to changes in insulin secretion. The overall objective of this proposal is to delineate the roles of circadian rhythmicity (intrinsic effects of time of day irrespective of the sleep condition), and sleep (intrinsic effects of the sleep condition irrespective of the time of day) in this physiological modulation of glucose levels. Our strategy will be quantify the diurnal variations of glucose levels and insulin secretion under a variety of conditions where circadian rhythmicity, sleep and counterregulatory hormones regulated by circadian rhythmicity (cortisol) or sleep (GH) are experimentally manipulated or pathologically altered. These conditions will include 1. dissociation between circadian rhythmicity and sleep by a 12- h shift of the sleep-wake cycle 2. sleep deprivation 3. circadian rhythm deprivation by exposure to bright light at specific times of day 4. amplification of diurnal rhythms of cortisol and GH using appropriately timed injections of CHR and GHRH respectively 5. aging, a state of reduced sleep efficiency, reduced circadian rhythmicity and reduced GH secretion 6. non-insulin-dependent diabetes (NIDDM), a state of glucose intolerance and excessive GH secretin. Frequent blood sampling, polygraphic sleep recordings, direct in vivo estimations of hormonal secretion and detailed mathematical analyses will be used to accurately delineate the temporal organization of the hormonal system controlling glucose levels in each of these conditions. The proposed studies will identify primary mechanisms involved in the normal physiological regulation of glucose levels and examine the role of sleep an circadian rhythms abnormalities in the pathogenesis of glucose intolerance in aging and NIDDM. Their results will provide the basic information necessary to optimize the diagnosis and treatment of conditions of impaired glucose tolerance with respect to time of day and to define strategies facilitating the adaptation to abrupt shifts of the sleep-wake cycle (such as occur in "jet lag") for subjects with NIDDM.

The proposed studies will delineate the roles of circadian rhythmicity (intrinsic effects of time of day irrespective of the sleep condition) and sleep (intrinsic effects of the sleep condition irrespective of the time of day) in the physiological modulation of glucose levels using a variety of conditions where circadian rhythmicity (cortisol) or sleep (GH) are experimentally manipulated or pathologically altered.

The objectives of this project are to determine the physiological mechanisms and functional significance of age-related changes in circadian rhythms and sleep and to examine the feasibility and efficacy of corrective strategies. Our long-term goal is to enhance the health and life quality of older adults by improving nocturnal sleep, decreasing daytime sleepiness and re-establishing the hormonal correlates of a normal sleep-wake cycle. This multidisciplinary project combines the efforts of investigators at the University of Chicago and at Northwestern University and includes non- invasive studies in subjects in assisted living facilities, Clinical Research Center studies of middle-aged and older adults, in vivo studies of circadian rhythmicity and sleep in hamsters and rats and in vitro molecular studies. Project #1 will determine whether the timings of photic and activity exposure are critical for their beneficial effects and explore the efficacy of strategies increasing the magnitude of non-photic inputs to consolidate sleep and improve daytime function in nursing home residents. Project #2 will test the hypothesis that midlife decreases in both non- photic and photic inputs to the circadian system may contribute to the development of alterations of circadian function, sleep and endocrine function in late life as well as explore strategies designed to restore exposure to non-photic and photic inputs to correct such alterations in midlife and late life. Project #3 will determine the chronology of age- related changes in the circadian system, test hypotheses regarding the role of Neuropeptide Y in causing alterations in non-photic inputs and explore corrective strategies involving increased exposure to both photic and non- photic inputs in hamsters. Project #4 will investigate the effect s of aging on the neural and molecular mechanisms subserving photic entrainment and examine the role of genetic factors in age-related changes in expression of circadian rhythmicity. Project #5 will determine the roles of age-related alterations in circadian rhythmicity and pineal function in causing sleep disturbances in rats. These five Project will be supported by three Cores. Core A (Administrative) will provide the overall logistical and financial coordination and assist in the recruitment of older volunteers. Core B (Methods and Analysis) will supply, operate and maintain the equipment used in the five Projects to monitor circadian rhythms and sleep in humans and rodents and provide methods for reporting and analyzing profiles of behavioral and physiological variables. Core C (Laboratory ) will assay blood and/or saliva levels of hormones for Projects #1, #2 and #3.

The Methods and Analysis Core has two main functions. First, to supply, operate and maintain the specialized equipment used in individual Research projects for monitoring a variety of overt circadian rhythms in rodents and humans, and to implement standard procedures for their computer storage. The Core also explores and validates novel techniques for non-invasive monitoring of overt circadian rhythms in humans and rodents. A second main function is to provide investigators in all five Projects with standard methods for reporting and analyzing temporal profiles of activity, temperature, sleep stages, hormonal levels, and behavioral variables. The Core also explores and validates novel methods for data analysis that are specially suited to the data obtained in the five Projects. The availability of a centralized pool of monitoring equipment prevents equipment duplication and provides the individual investigators with expert assistance for optimal operation and trouble-shooting of the equipment. The availability of standardized procedures for data reporting and analysis enables each investigator to extract as much information as possible from the collected data, and facilitates the integration of individual projects as well as communication between investigators. Standardization of data processing and analysis enables additional comparisons of various study groups across Projects, and thus more information can be derived from the Program Project as a whole than from the sum of each of its components. This core has also enabled the various projects to incorporate a variety of new approaches for recording and analyzing sleep and circadian rhythms. Of particular significance is the development of new approaches over the past 18 months for; 1) the quantitative analysis of circadian pattern fragmentation, 2) the use of a nw device for monitoring alertness under ambulatory conditions, 3) monitoring a range of cognitive functions, and 4) the recording of EEG and EMG waveforms in the hamster using a state-of- [unreadable]he-art system. The use of these and other new approaches developed by t his core will greatly enhance the overall quality and quantity of the data collected in the five projects.

In older adults, nocturnal sleep is often shallow and fragmented and this is associated with decreased daytime alertness. The timing of sleep is also modified, with earlier bedtimes and morning awakenings. Earlier timing and reduced amplitude have also been observed for other 24-hour rhythms, including those of hormonal secretions. These alterations are thought to reflect age-related changes i the brain mechanisms controlling circadian rhythmicity and/or the sleep/wake state. These two systems interact, as circadian rhythmicity modulates the timing and duration of sleep and the sleep-wake cycle in turn exerts synchronizing (i.e. zeitgeber) effects on the circadian pacemaker. The other major zeitgeber for circadian rhythmicity is the light-dark cycle. Recent research has indicated that age-related alterations in exposure and response to non- photic and photic zeitgebers may be more severe than alterations in intrinsic pacemaker function and/or chronologically precede such alterations. The present project will: 1. test the hypothesis that decreases in both non-photic inputs (slow-wave activity and ability to recover from sleep loss) and photic inputs (diminished melatonin suppression and/or reduced ability to phase-shift in response to light exposure) may be already present in midlife and contribute to the development of alterations of circadian rhythmicity, sleep and endocrine function in late life; 2. explore strategies designed to restore exposure to non-photic inputs (by restoring slow-wave activity and the associated GH secretion and photic inputs (by restoring nocturnal melatonin levels similar to those observed in young subjects using a transmucosal melatonin patch applied to th gum) to correct alterations of circadian rhythmicity, sleep and endocrine function in midlife and late life. These studies will test the hypothesis that the senescence of the sleep and/or circadian systems in partially responsible for age-related dysfunctions in hormonal secretions, delineate the earliest alterations in the circadian/sleep systems occurring in course of aging and provide information regarding athe feasibility and efficacy of preventive or corrective strategies.

The primary goal of this protocol is to delineate the synchronizing effects of exposure to exercise and darkness on the human circadian system and to test the hypothesis that additive effects of adequately timed exposure to pulses of bright light, darkness and exercise may result in large and rapid phase-shifts of human rhythms.

This is a double-blind, placebo controlled, multi-center study testing the hypothesis that 2 weeks of treatment with 25 mg MK-0677, an orally active growth hormone secretagogue, will have beneficial effects on sleep quality in older adults with sleep complaints.

These studies will test the hypothesis that age-related decreases in the nocturnal secretion of GH and melatonin contribute to diminished sleep duration and quality diminished daytime alertness and to the disorders of circadian amplitude and phase which characterize older adults.

hypothalamic pituitary adrenal axis; glucose tolerance; functional ability; sleep deprivation; cognition; cognition disorders; metabolism disorder; endocrine gland /system; human subject;

[unreadable] DESCRIPTION (provided by applicant): Extended work schedules almost invariably result in reduced time for sleep. Work schedules that produce the shortest sleep times are those of night workers. In addition to sleep loss, shift work also results in chronic maladaptation of circadian rhythms. Recent studies have demonstrated that sleep loss has an adverse health impact and may represent a risk factor for obesity, hypertension and diabetes. Whether circadian maladaptation, independently of sleep loss, also has negative health consequences is not known. The overall goal of the present proposal is to test the hypothesis that sleep loss as occurs during extended work schedules may result in adverse health consequences. We propose to use two experimental protocols, each involving 8 days of bedtime curtailment to model in the laboratory the amount of sleep loss typically associated with extended work schedules. The first protocol simulates a schedule of regular extended daytime hours and restricted nighttime sleep. The second protocol simulates a work schedule alternating between day work and night work. The total number of bedtime hours during the experimental period is identical in both models and, because of the restricted bedtimes (5 hours), it is expected that the total amount of sleep occurring during the 8-day experimental period will be similar in both models. Glucose tolerance, neuroendocrine profiles, cardiovascular function, and neurobehavioral parameters will be measured under baseline conditions and at the end of the 8-day experimental period. Two groups of gender- and age-matched healthy subjects will be studied under each protocol in order to allow for the testing of gender differences and impact of circadian disruption independently of sleep loss. The results of the proposed studies are expected to provide an estimation of sleep loss and circadian disruption as risk factors for the health and well-being of many Americans who work long and/or irregular hours.

DESCRIPTION (provided by applicant): Chronic sleep disturbance is reported by nearly 50% of older adults. Sleep loss also occurs at all ages due to bedtime curtailment, an increasingly prevalent condition. Recent data have revealed the role of sleep duration and quality in metabolic and endocrine function and have indicated that chronic sleep loss may accelerate the development or increase the severity of age-related diseases such as obesity and diabetes. Despite its high prevalence, chronic sleep loss has been understudied. The present Project focuses on the interaction of chronic partial sleep loss and aging. A multi-disciplinary approach combining epidemiology, clinical research (in older insomniacs, middle-aged subjects at risk for obesity and healthy adults of all ages), in vivo studies in laboratory rodents and molecular and genetic analyses will be used to: 1. Delineate the impact of age on sleep regulation during adaptation to and recovery from chronic partial sleep loss; 2. Test the hypothesis that chronic partial sleep loss has adverse effects on biomarkers of aging and increases the risk of obesity and diabetes; 3. Test the hypothesis that paying a sleep debt and/or improving sleep quality has beneficial health and neurobehavioral effects at all stages of adulthood; 4. Determine the influence of the circadian clock on the response to chronic sleep loss; 5. Explore the mechanisms linking chronic sleep loss and metabolic aging; 6. Define the determinants of individual differences in sleep capacity and vulnerability to sleep loss in young adulthood, midlife and late life. Project 6 will determine the role of sleep in weight gain in mid life. Project 7 will examine whether exercise is an effective countermeasure for sleep loss in older insomniacs. Project 8 will delineate the role of sleep duration in metabolic aging and weight gain. Project 9 will determine the impact of a sleep debt and individual sleep capacity in young, middle-aged and older men and women. Project 10 will use rat models to define the impact of age on physiologic adaptation to and recovery from sleep restriction. Project 11 will utilize a genetic model of chronic sleep loss with age-related obesity, the Clock mouse, to explore mechanisms linking circadian function, sleep and metabolism. Core 9001 (Methods and Analysis) will provide monitoring equipment for humans and rodents, methods for quantifying output variables and biostatistical support. Core 9002 (Laboratory) will assay blood, saliva and urine constituents for Projects 7, 8 & 9.

pituitary dwarfism; sleep; disease /disorder etiology; quality of life; human therapy evaluation; epidemiology; somatotropin; hormone therapy; hypothalamus; endocrine disorder chemotherapy; pituitary gland; attention; psychological adaptation; patient oriented research; clinical research; adult human (21+); human subject;

glucose tolerance; health behavior; sleep; education evaluation /planning; sleep deprivation; health education; noninsulin dependent diabetes mellitus; prediabetic state; behavioral medicine; human therapy evaluation; diabetes mellitus therapy; patient oriented research; glucose tolerance test; human subject; clinical research;

glucose tolerance; sleep deprivation; sleep; endocrinology; age difference; gender difference; health behavior; clinical research; human subject;

sleep deprivation; sleep; endocrinology; metabolism; health behavior; clinical research; human subject;

DESCRIPTION (provided by applicant): There is increasing evidence from both epidemiologic and laboratory studies for an association between sleep duration and/or quality and the prevalence and/or severity of major chronic diseases, including diabetes and cardiovascular disease. Sleep disturbances, particularly sleep disordered breathing (SDB) and periodic leg movements (PLM), are more prevalent in patients with chronic kidney disease (CKD) than in the general population. Because the hormones involved in the control of kidney function are markedly modulated by sleep, it is possible that sleep disturbances have an adverse effect on kidney function. The present proposal therefore seeks to explore the role of decreased sleep duration and/or quality as a risk factor for the progression of chronic renal insufficiency and the development of cardiovascular disease in CKD. This study has two over-arching hypotheses: 1. Sleep quality will be a predictor of the progression of CKD, and 2. Sleep quality will be a predictor of cardiovascular disease in CKD. This project will be an ancillary study to an ongoing longitudinal cohort study, the Chronic Renal Insufficiency Study (CRIC). Specific Aim 1 will involve assessment of habitual at-home sleep duration and quality (by wrist and leg activity monitoring, logs and questionnaires) to predict changes in renal and cardiovascular measures over study period in CRIC subjects. Specific Aim 2 will examine changes in polysomnographic variables, including measures of SDB and PLM, to predict changes in renal and cardiovascular measures over study period in CRIC subjects. Specific Aim 3 will delineate the relationship between hormones controlling body fluid balance, cardiovascular function and sleep in mild to moderate CKD patients as compared to normal controls to identify possible pathophysiological mechanisms. Overall, the proposed studies will determine if poor sleep quality accelerates the development or increases the severity of CKD and of cardiovascular disease in CKD and if strategies to improve sleep quality may have beneficial effects on CKD.

DESCRIPTION (provided by applicant): Our group has identified reduced sleep duration as a novel risk factor for obesity and type 2 diabetes. During the previous grant period, we have shown that reduced sleep quality, specifically reduced deep slow-wave sleep (SWS), has adverse cardiometabolic consequences and obtained evidence that a "vicious cycle" may interconnect sleep and circadian disruption with cardiometabolic disease. In both humans and rodents, we further observed that chronic partial sleep restriction alters the homeostatic regulation of sleep, a phenomenon that may be referred to as an "allostasis" of sleep regulation. Normal aging is associated with reductions in sleep duration, sleep quality and circadian function. The present Program Project focuses on the interactions between chronic reductions of sleep duration, sleep quality and circadian function and the age-related increase in cardiometabolic disease. A multi-disciplinary approach combining statistical analyses of a large data set, clinical research (in healthy adults of all ages, older insomniacs, and older adults with sleep disturbances), in vivo studies in a rodent model of chronic partial sleep loss and molecular and genetic analyses will be used to: 1. test the hypothesis that individuals with low SWS because of age, ethnicity or genetic factors, are at higher risk for type 2 diabetes (human studies, E. Van Cauter, PI);2. test the hypothesis that the preservation or restoration of SWS has beneficial cardiometabolic effects (human studies, E. Tasali, PI);3. test the hypothesis that the most common types of insomnia in older adults are associated with reduced SWS and cardiometabolic alterations (human studies;P.C. Zee, PI);4. perform a comprehensive evaluation of the impact of age on sleep allostasis during chronic partial sleep restriction and determine the cardiometabolic consequences (rat studies;F.W. Turek, PI);5. dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss (mouse studies;J. Bass, PI). Core A (Administrative) will provide logistic and financial coordination. Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents.

Our group has identified reduced sleep duration and reduced sleep quality as novel risk factors for type 2 diabetes. Type 2 diabetes develops when the pancreatic beta cells fail to release enough insulin to compensate for the degree of insulin resistance of peripheral tissues. Reductions in sleep duration or in sleep quality both result in increased insulin resistance without appropriate compensation by beta cell release. We have further obtained evidence indicating that beta cell function in young healthy adults is strongly correlated with baseline levels of slow-wave activity (SWA; EEG spectral power in the 0.5-4 Hz range), the primary marker of sleep-wake homeostasis. Studies completed during the previous grant period have, however, shown that during repeated partial sleep deprivation, SWA does not increase despite the increased cumulated duration of wakefulness. This allostasis of SWA with recurrent sleep loss could accelerate age-related declines in the homeostatic control of sleep. SWA decreases markedly with age and sex differences have been well-recognized. We have recently identified robust ethnic differences in SWA, with African-Americans having lower levels of SWA than whites. SWA is a remarkably stable trait-dependent characteristic that varies greatly from one individual to another. Heritability of SWA has not yet been evaluated. The overall goal of this project is to test the hypothesis that individuals with low SWA, because of age, ethnicity, sex or genetic factors, are more susceptible to develop type 2 diabetes because they have reduced beta cell function and, therefore a higher vulnerability to the metabolic challenge of sleep disturbances. To achieve this goal, we will combine statistical analyses of the very large data base accumulated from studies conducted by our group during the past 10 years, with a direct experimental approach and an exploration of genetic factors that could underlie both the regulation of SWA and genetic susceptibility to diabetes. The findings from this project are expected to demonstrate the importance of preserving or improving sleep quality to reduce the risk of type 2 diabetes. RELEVANCE (See instructions): The incidence of type 2 diabetes is increasing in the U.S. and worldwide. This project will determine the role of reductions in sleep duration and quality in the risk of type 2 diabetes. The findings could lead to novel strategies to delay the development or reduce the severity of type 2 diabetes.

DESCRIPTION (provided by applicant): Nearly 20% of the US working population is engaged in shift work. It is well recognized that shift work is associated with an increased risk of developing cardiovascular disease and diabetes but the mechanisms underlying this elevated cardiometabolic risk remain unclear. Shift work is generally associated with sleep loss and circadian misalignment. While sleep curtailment has been recently identified as a putative novel risk factor for obesity, diabetes and hypertension, the clinical significance of the internal synchrony of endogenous rhythms is a fundamental and as yet unanswered question of circadian biology. Our group has recently completed a laboratory study showing that short-term exposure to sleep loss with circadian misalignment is associated with cardiometabolic alterations that are not reversed when sleep is aligned and extended. By comparison, alterations observed following exposure to sleep loss without circadian misalignment are fully corrected after sleep extension. These laboratory findings provided for the first time evidence in support of adverse health consequences of circadian disruption independent of sleep loss. The overall goal of the present application is to test the hypothesis that shift workers, who are chronically exposed to circadian misalignment and sleep loss, have a higher cardiometabolic risk than day workers, and that both circadian misalignment and sleep loss contribute to the elevated cardiometabolic risk. We will measure markers of cardiometabolic risk that are rapidly and profoundly affected by reduced sleep duration and/or quality and perform a detailed assessment of the phase relationships between rhythms controlled by the central circadian pacemaker and rhythms of clock gene expression in peripheral tissue. We propose to study two groups of workers (i.e. day workers, shift workers) who are employed at the University of Chicago Medical Center and who have maintained their work schedules for at least one year. Following extended ambulatory monitoring of exposure to circadian misalignment and usual sleep duration, the subjects will undergo repeated detailed laboratory assessments of 1. internal desynchrony of circadian rhythms, including rhythms of circadian gene expression in leukocytes; 2. markers of cardiometabolic risk: glucose tolerance and insulin resistance assessed by intravenous glucose tolerance testing (ivGTT), high sensitivity C-reactive protein (hsCRP), 24-h profile of heart rate variability; 3. telomere length and telomerase activity in leukocytes, which are markers of biological aging that have been linked to cardiometabolic risk factors and are influenced by lifestyle. This work is expected to demonstrate the clinical significance of circadian misalignment for the millions of individuals involved in shift work and to suggest novel strategies to improve tolerance to shift work. Public Health Relevance: Nearly 20% of the US working population is engaged in shift work, a condition associated with an increased risk of developing cardiovascular disease and diabetes. The overall goal of this project is to define the respective roles of circadian misalignment versus sleep loss in the elevated cardiometabolic risk of shift work.

The Administrative Core provides the overall logistic and financial coordination to the Program Project, facilitates the scientific and administrative interactions between the various Projects and Cores, prepares fiscal and narrative reports, and ensures that the studies are performed in a cost- effective manner. The Administrative Core also supervises recruitment efforts of study subjects for the three clinical research projects. The Core orders supplies and equipment, coordinates inter- institutional and inter-departmental relationships within the Program Project and organizes all meetings related to the Program Project. The Administrative Core is run by the Principal Investigator (Eve Van Cauter) with the assistance of the co-principal investigator (Fred W. Turek). The Steering Committee includes all the project leaders and core directors and serves to evaluate the integration, direction and progress of research activities and the efficient allocation of and use of resources and services. The Program Project is reviewed in years 2, 3 and 5 by a three member External Review Committee. The Administrative Core serves all fives projects as well as the Methods and Analysis Core and the Laboratory Core. The Administrative Core facilitates the integration and efficiencyof the Program project as a whole. RELEVANCE (Seeinstructions): The Methods and Analysis Core will play a crucial role in the improvement of recording, archival and analysis procedures, and will be a major source for cross-fertilization of concepts and methods.

DESCRIPTION (provided by applicant): Prevention of T2DM is a critical and attainable goal Interventions to prevent or delay development of T2DM in those with prediabetes have focused on reducing insulin resistance via lifestyle modification, the use of insulin lowering medications, or both. The introduction of incretin therapies, e.g., GLP agonists, makes it possible to determine if similar or superior outcomes can be achieved with strategies to preserve or enhance insulin secretion. The overall goal of this randomized clinical trial is to determine whether the expected augmentation in insulin secretion imparted by administration of liraglutide will be enhanced by the co-administration of pioglitazone, an insulin sensitizer that will "unburden the beta cell" and preserve beta cell function. This combination will be compared to liraglutide+placebo to determine whether the effects of pioglitazone, if any, are additive to or synergistic with those of liraglutide. A unique aspect of our approach is that, whenever applicable, CPAP treatment of OSA, an independent risk factor for insulin resistance, will be incorporated into the treatment paradigm and will serve as a covariate in the analysis of the response to pharmacologic therapy. All participants will be assessed at baseline and 26 wks post-treatment with: a 75gm 5-h OGTT analyzed by the modified minimal model, an isoglycemic glucose infusion to estimate the incretin effect, a fsIVGTT to estimate AIRg and Si, and a graded glucose infusion to assess beta cell function. We will target individuals with high rates of prediabetes and T2DM: adults with a first-degree relative with T2DM, women with a prior history of GDM, women with PCOS, and overweight and obese individuals aged >45 yr. The following Specific Aims will be addressed: Specific Aim 1. To determine if 26 wks of treatment with liraglutide+pioglitazone is superior to liraglutide+placebo in improving insulin secretion in individuals with prediabetes or recent-onset T2DM. Specific Aim 2: To determine if beta cell responsiveness to two different modalities of pharmacologic intervention (liraglutide alone and liraglutide+pioglitazone) is modulated by the presence of OSA and by African-American race/ethnicity. Specific Aim 3: To determine if treatment of OSA by CPAP preserves or enhances beta cell function in the absence of pharmacological treatment and if the impact of OSA on insulin secretion and action is modulated by race. Specific Aim 4: To determine if 26 wks of liraglutide+ pioglitazone is superior to liraglutide+placebo in extending the durability of drug treatment on beta cell function. PUBLIC HEALTH RELEVANCE (provided by applicant): The proposed studies in this application bring a new dimension to the evaluation and understanding of the role of the beta cell in the pathogenesis of prediabetes and T2DM. Innovative aspects include the choice of the drug combination to be tested;detailed simultaneous assessment of the main components of glucose tolerance (beta cell responsiveness to oral and intravenous glucose challenges, insulin sensitivity, and incretin effect);and lastly to the critical evaluation of OSA as a modifier of inulin secretion and insulin action among subjects predisposed to develop T2DM. NOTE: The critiques below were prepared by the reviewers assigned to this application. These commentaries may not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representations of the final outcome of group discussion. If there is any discrepancy between the peer reviewers'commentaries and the numerical score on the face page of this summary statement, the numerical score should be considered the most accurate representation of the final outcome of the group discussion.

DESCRIPTION (provided by applicant): This is a resubmission of a renewal application for continued support of an established T32 Training Grant in Circadian and Sleep Research to train and support predoctoral and postdoctoral students at Northwestern University (NU) and the University of Chicago (U of C). The integration of circadian biology and sleep research in both animal models and humans has been the cornerstone of the relationship between the preceptors on this Training Grant at the U of C and NU for over 20 years, and we have added the term circadian to the title of our Training Program in recognition of the importance of combining these fields in the training of the next generation of young investigators. This Training Program will be led by two established senior investigators under the Multiple Leadership Plan and will involve 13 Primary Training Faculty who have their primary appointments in either basic science or clinical departments. The proposed Training Program will offer predoctoral and postdoctoral students interdisciplinary and multidisciplinary training in a wide range of scientifi disciplines that are highly relevant to understanding the function, regulation and health implications of sleep and circadian rhythmicity. Central to this Program is the training of student in modern basic science, translational research as well as patient oriented research. Multiple research perspectives have fueled for more than a decade the productive interactions and cross-fertilization that have developed between the preceptors in this Program. During the current grant period, the scope of the research activities of the Training Faculty has expanded to include bench to bedside investigations of the impact of sleep-disordered breathing on metabolism and cardiovascular function and we propose to further broaden the program in our renewed program with the addition of six outstanding physician-scientists to the training faculty. As our nation is facing unprecedented epidemics of obesity, diabetes and their cardiovascular consequences, the Training Program proposed in the present application is uniquely positioned to train an interdisciplinary workforce of academic and industry investigators as well as government decision makers to address the roles of sleep disturbances and circadian dysfunction in these public health challenges. A key feature of our Training Program is the inclusion of 10 Collaborating Faculty with additional clinical, scientific and/or educational expertise that greatly enhances our training environment, and conversely, they will benefit from their participation in the program by developing mentoring skills. Our Program will enable trainees to integrate cutting edge approaches and techniques in the areas of genetics, genomics, endocrinology, metabolism, pharmacology, neurobiology, pulmonology, cognitive neuroscience, gerontology and chronobiology into their training in sleep and circadian research. Because the preceptors in this Training Program are actively involved in research at the molecular, cellular, systems, behavioral and epidemiological levels, trainees will be trained in a rich environment of activities that are integrated together for the study of the basic mechanisms of sleep and circadian function at all levels of biological organization.

The circadian system is a hierarchical organization with a master pacemaker in the hypothalamus (the SCN) and peripheral clocks in many, if not all, other tissues. Although the light-dark cycle is the primary external synchronizer of the SCN, the timing of food intake is a powerful synchronizer of many peripheral clocks. The connections between the central SCN clock, behavioral rhythms such as sleep-wake and feeding cycles, and peripheral clocks are not fully understood. These connections therefore constitute a novel, translational research focus for human health and disease. Our project will examine the effect of interventions to impact peripheral rhythms through manipulation of feeding. Previous clinical and observational research studies of circadian rhythms and chronotype indicate that misalignment of central and peripheral clocks has adverse health consequences, including an increase in cardio-metabolic risk. However, little is known about the impact of aging on the overall synchronization of central and peripheral clocks, particularly the role of dietary time cues. Age- related reductions in amplitude and regularity of external and internal synchronizing signals may adversely impact synchrony of peripheral clocks. Reduced synchrony of peripheral signals may in turn contribute to age- related changes in sleep homeostasis. Circadian disruption may accelerate metabolic aging, both directly and indirectly by affecting sleep-wake homeostasis. Conversely, behavioral strategies to optimize circadian organization may decrease the risk of weight gain, diabetes and their cardiovascular consequences. Our proposed project focuses on the impact of dietary alignment of peripheral oscillators on cardio-metabolic risk, sleep quality and the overall synchronization of the circadian system. The overall goal of the project is to determine whether there is an optimal alignment of eating behavior (?dietary chronotype?) with sleep-wake behavior (?sleep chronotype?) and the central circadian signal (as assessed via the melatonin onset [DLMO]) that minimizes cardio-metabolic risk in middle-aged (35 ? 50 y) and older (55 ? 75 y) adults. We will use a 5-day intervention to test the hypothesis that extending and anchoring the overnight fast, independently from the timing of daytime food intake, has beneficial effects on cardio-metabolic risk, sleep quality and the alignment of rhythmic outputs of central and peripheral clocks. This first intervention will be followed by a second intervention that will test the hypothesis that early versus late timing of daytime dietary intake, without change in the timing or duration of the overnight fast, have distinct and opposite effects on cardio-metabolic risk, sleep quality and overall circadian alignment. Diabetes risk will be assessed by a 5-hour oral glucose tolerance test (OGTT). Nocturnal blood pressure dipping will be our primary cardiovascular outcome. Slow-wave activity and wake after sleep onset will be our primary sleep quality outcomes. Overall circadian alignment will be assessed using phase markers of the 24-hour profiles of melatonin, cortisol and leptin. Exploratory measures will include levels and rhythmicity of NAD+ in blood cells coupled with assessment of resting metabolic rate.

The Methods and Analysis Core will have five main functions and serve all three projects of the Program Project. A first function of the Core will be to continue to implement and update standard operating procedures for the collection of PSG signals, metabolic measures, cardiovascular measures, hormonal profiles and neurobehavioral tests. Particular attention will be paid to adequate time synchronization with the other biological and psychological measurements. A second function of Core B will be to establish and manage a shared data repository to centralize digital records (PSG, cardiometabolic, hormonal and neurobehavioral measures) obtained during the past and current project periods. The repository will be located on a server at the University of Chicago and all project investigators will have remote access using encrypted authentication. A third function of Core B will be to provide specific computerized analytical tools (PRANA software, Chronobiological Series Analyzer (CSA), Minimal Model Software [MiniMod], Templates for analysis of oral glucose tolerance tests) for the scoring of human and animal sleep-wake stages, the edition of sleep transient events, and the analysis of hormonal, cardiovascular, genetic and metabolic data. Fourth, the Core will develop new computerized tools for analyzing temporal profiles of gene expression. Lastly, Core B will provide expert statistical support to the different projects. The functions served by the Methods and Analysis Core will greatly enhance the overall quality, originality and quantity of the data collected in the individual projects.