The purpose of this proposal is two-fold: (1) to provide protected time and support to Dr. Klerman while she mentors graduate students, post-doctoral fellows and junior faculty towards careers in patient-oriented research;and (2) to conduct patient-oriented research related to the effects of light on multiple physiologic functions. Dr. Klerman is actively involved in both patient-oriented experimental work and mathematical analyses and modeling that will enable translation of research results into real-world applications. The mammalian eye serves both visual and non-image-forming functions. Some of the non-visual responses are due to the effect of light on circadian rhythms, the endogenous ~24-hour rhythms generated by a pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). Disruption of the circadian pacemaker or of its normal phase relationship with local time, such as with night or rotating work shifts or jet lag, is associated with illness, errors and accidents. Other non-visual effects of ocular light exposure include melatonin suppression (as a signal for seasonal reproductive changes), pupillary reflexes, and changes in heart rate, performance, and alertness. The SCN receives ocular light stimuli primarily mediated by intrinsically photosensitive retinal ganglion cells, rather than rod and cone photoreceptors. The outputs of the SCN influence almost every physiologic function, including the timing and content of sleep, hormone release, cardiovascular and gastrointestinal function, objective performance, subjective alertness, and mood. We will quantify the effects of light on circadian rhythms and other physiologic functions using experimental, modeling, and database approaches. Experimentally, we will document the effects of short duration light stimuli and the duration of darkness exposure required to reset circadian sensitivity. The data from these experiments will be combined into a database with data from over 2000 subjects already studied in similar protocols. All these data then will be used to refine our validated mathematical model of the effects of light on the human circadian pacemaker. This model and a linked model of circadian and sleep-wake schedule effects on performance and alertness with countermeasure applications will be made available on the internet. The activities outlined in this proposal have implications for science, for public health, and operational (work) situations. The mentoring work will address a critical shortage of researchers in sleep and circadian rhythms, documented in a US Department of Health and Human Services-sponsored National Center on Sleep Disorders Research report. The experimental work is relevant both for understanding the basic physiology of human circadian, hormone, heart rate, performance and alertness functions and for patient-oriented research including retinal/eye care and sleep of older persons. The results can be used to make predictions about the effects of light, to make recommendations involving exposure to or avoidance of light, and to design environmental lighting, resulting in improved health and alertness and decreased errors and accidents.

Public Health Relevance

The purpose of this proposal is two-fold: (1) to provide protected time and support to Dr. Klerman as she continues mentoring graduate students, post-doctoral fellows and junior faculty towards careers in patient- oriented research;and (2) to quantify the effects of short light stimuli on human circadian rhythms, performance, alertness, and other physiologic functions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Twery, Michael
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Brigham and Women's Hospital
United States
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Klerman, Elizabeth B; Beckett, Scott A; Landrigan, Christopher P (2016) Applying mathematical models to predict resident physician performance and alertness on traditional and novel work schedules. BMC Med Educ 16:239
Shaw, Natalie D; McHill, Andrew W; Schiavon, Michele et al. (2016) Effect of Slow Wave Sleep Disruption on Metabolic Parameters in Adolescents. Sleep 39:1591-9
Bermudez, Eduardo B; Klerman, Elizabeth B; Czeisler, Charles A et al. (2016) Prediction of Vigilant Attention and Cognitive Performance Using Self-Reported Alertness, Circadian Phase, Hours since Awakening, and Accumulated Sleep Loss. PLoS One 11:e0151770
Lane, Jacqueline M; Chang, Anne-Marie; Bjonnes, Andrew C et al. (2016) Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology. Diabetes 65:1741-51
Sano, Akane; Yu, Amy Z; McHill, Andrew W et al. (2015) Prediction of Happy-Sad mood from daily behaviors and previous sleep history. Conf Proc IEEE Eng Med Biol Soc 2015:6796-9
Faghih, Rose T; Dahleh, Munther A; Adler, Gail K et al. (2015) Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing. IEEE Trans Biomed Eng 62:2379-88
Vijayan, Sujith; Klerman, Elizabeth B; Adler, Gail K et al. (2015) Thalamic mechanisms underlying alpha-delta sleep with implications for fibromyalgia. J Neurophysiol 114:1923-30
Balasubramanian, Ravikumar; Cohen, Daniel A; Klerman, Elizabeth B et al. (2014) Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2. J Clin Endocrinol Metab 99:E561-6
Faghih, Rose T; Dahleh, Munther A; Adler, Gail K et al. (2014) Deconvolution of serum cortisol levels by using compressed sensing. PLoS One 9:e85204
Dean 2nd, Dennis A; Adler, Gail K; Nguyen, David P et al. (2014) Biological time series analysis using a context free language: applicability to pulsatile hormone data. PLoS One 9:e104087

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