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. Narrative 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)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL105664-05
Application #
8709862
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Twery, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
Phillips, A J K; Fulcher, B D; Robinson, P A et al. (2013) Mammalian rest/activity patterns explained by physiologically based modeling. PLoS Comput Biol 9:e1003213
Breslow, Emily R; Phillips, Andrew J K; Huang, Jean M et al. (2013) A mathematical model of the circadian phase-shifting effects of exogenous melatonin. J Biol Rhythms 28:79-89
Phillips, A J K; Robinson, P A; Klerman, E B (2013) Arousal state feedback as a potential physiological generator of the ultradian REM/NREM sleep cycle. J Theor Biol 319:75-87
Klerman, Elizabeth B; Wang, Wei; Duffy, Jeanne F et al. (2013) Survival analysis indicates that age-related decline in sleep continuity occurs exclusively during NREM sleep. Neurobiol Aging 34:309-18
Klingman, Kara M; Marsh, Erica E; Klerman, Elizabeth B et al. (2011) Absence of circadian rhythms of gonadotropin secretion in women. J Clin Endocrinol Metab 96:1456-61
Phillips, Andrew J K; Czeisler, Charles A; Klerman, Elizabeth B (2011) Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology. J Biol Rhythms 26:441-53