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Casein Kinase 1, Alcohol Abuse and Comorbid Sleep and Circadian Disturbances

Award Number: R21AA023078
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2017

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Casein Kinase 1, Alcohol Abuse and Comorbid Sleep and Circadian Disturbances - DESCRIPTION (provided by applicant): Chronic alcohol abuse is associated with many physiological disturbances, resulting in numerous sleep disruptions, circadian desynchrony, and circadian clock gene dysregulation that may aggravate alcohol's negative effects and potentiate alcohol dependence. Circadian clock genes such as per2 are known to influence the development of alcohol abuse. Casein-kinase-1 epsilon and delta (CK1????), key post- translational players in the molecular circadian clock, regulates the availability of the clock protein PER2. CK1??? have been implicated in sleep disorders as well as in drug abuse-related behaviors. I have recently shown that systemic administration of PF-670462, a CK1???? inhibitor, prevents alcohol relapse-like drinking in chronic alcohol self-administering rats (Neuropsychopharmacology, 2012). The goal of the proposed research is to further test the beneficial effects of CK1???? inhibition on alcohol abuse and comorbid sleep and circadian disturbances and provide insight into the neurobiological mechanisms involved. We will test whether the beneficial effect of CK1???? inhibition observed on alcohol relapse can be replicated and affect other behaviors leading to alcohol dependence (e.g. alcohol binge-drinking). We hypothesize that (1) repeated alcohol binge-drinking episodes will affect the circadian period of locomotor activity and induce sleep disturbances, and (2) CK1???? inhibition will decrease alcohol binge-drinking, restore the circadian period and ameliorate the disrupted effects on sleep. Based on our preliminary results, we further hypothesize that the protective effect of CK1???? inhibition on alcohol consumption is mediated via the CK1?? isoform; and that CK1?? will affect alcohol binge drinking and subsequent circadian and sleep disturbances via the regulation of PER2 availability. In Year 1, we will test the hypothesis that CK1???? inhibition will reduce alcohol binge drinking and normalize circadian function and sleep disruption in C57BL/6J mice. We will use a binge-drinking mouse protocol, called "drinking-in-the-dark" (DID), where multiple cycles of 4- days alcohol access followed by 2-bottle free choice alcohol access will occur over the course of weeks. We will additionally test if PF-670462 (1) dose-dependently reduces alcohol intake during binge drinking and subsequent free access to alcohol, (2) improves comorbid circadian dysfunction (e.g. free-running period and PER2 expression) and (3) ameliorates the expected sleep disturbances. In Year 2, we will use humanized hPER2S662G transgenic mutant mice to test whether a specific mutation of a CK1?? active binding site (S662) on the PER2 protein predisposes for alcohol binge-drinking. Alcohol intake, circadian function and sleep-wakefulness will be assessed using our established protocol. These results will provide insight into the role of CK1???? in alcohol abuse, circadian rhythms and sleep mechanisms. Evaluation of the role of CK1???? in the binge drinking model will help determine the utility of CK1???? as a pharmaceutical target for the treatment of alcoholism.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$698 )
2018	2015	SRI INTERNATIONAL	333 RAVENSWOOD AVE	MENLO PARK	CA	94025	SAN MATEO	USA	Alcohol Research Programs	000	2	12/18/2017	NON-COMPETING CONTINUATION	-$698
														Subtotal = -$698

Issue Date FY: 2015 ( Subtotal = $217,942 )
2015	2015	STANFORD RESEARCH INSTITUTE INTERNATIONAL	333 RAVENSWOOD AVENUE, AG139	MENLO PARK	CA	94025	SAN MATEO	USA	Alcohol Research Programs	000	2	7/22/2015	NON-COMPETING CONTINUATION	$217,942
														Subtotal = $217,942

Issue Date FY: 2014 ( Subtotal = $267,626 )
2014	2014	STANFORD RESEARCH INSTITUTE INTERNATIONAL	333 RAVENSWOOD AVENUE, AG139	MENLO PARK	CA	94025	SAN MATEO	USA	Alcohol Research Programs	000	1	8/5/2014	NEW	$267,626
														Subtotal = $267,626

Grand Total All Awards = $484,870

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Casein Kinase 1, Alcohol Abuse and Comorbid Sleep and Circadian Disturbances

Award Number: R21AA023078

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/05/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2017

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