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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24HL105664-01
Application #
8028932
Study Section
Special Emphasis Panel (ZHL1-CSR-X (O1))
Program Officer
Lewin, Daniel S
Project Start
2010-09-16
Project End
2015-07-31
Budget Start
2010-09-16
Budget End
2011-07-31
Support Year
1
Fiscal Year
2010
Total Cost
$166,802
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
McHill, Andrew W; Hull, Joseph T; McMullan, Ciaran J et al. (2018) Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones. Front Endocrinol (Lausanne) 9:319
Sano, Akane; Taylor, Sara; McHill, Andrew W et al. (2018) Identifying Objective Physiological Markers and Modifiable Behaviors for Self-Reported Stress and Mental Health Status Using Wearable Sensors and Mobile Phones: Observational Study. J Med Internet Res 20:e210
Asgari-Targhi, Ameneh; Klerman, Elizabeth B (2018) Mathematical modeling of circadian rhythms. Wiley Interdiscip Rev Syst Biol Med :e1439
McHill, Andrew W; Hull, Joseph T; Wang, Wei et al. (2018) Chronic sleep curtailment, even without extended (>16-h) wakefulness, degrades human vigilance performance. Proc Natl Acad Sci U S A 115:6070-6075
Bianchi, Matt T; Phillips, Andrew J K; Wang, Wei et al. (2017) Statistics for Sleep and Biological Rhythms Research. J Biol Rhythms 32:7-17
Phillips, Andrew J K; Clerx, William M; O'Brien, Conor S et al. (2017) Irregular sleep/wake patterns are associated with poorer academic performance and delayed circadian and sleep/wake timing. Sci Rep 7:3216
Rahman, Shadab A; St Hilaire, Melissa A; Chang, Anne-Marie et al. (2017) Circadian phase resetting by a single short-duration light exposure. JCI Insight 2:e89494
Gu, Fangyi; Xu, Shangda; Devesa, Susan S et al. (2017) Longitude Position in a Time Zone and Cancer Risk in the United States. Cancer Epidemiol Biomarkers Prev 26:1306-1311
Phillips, Andrew J K; Klerman, Elizabeth B; Butler, James P (2017) Modeling the adenosine system as a modulator of cognitive performance and sleep patterns during sleep restriction and recovery. PLoS Comput Biol 13:e1005759
McHill, Andrew W; Phillips, Andrew Jk; Czeisler, Charles A et al. (2017) Later circadian timing of food intake is associated with increased body fat. Am J Clin Nutr 106:1213-1219

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