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NEUROPATHOLOGY OF HYPOCRETIN

Award Number: R01NS014610
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/1983
PERIOD OF PERFORMANCE END DATE: 12/31/2014

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NEUROPATHOLOGY OF HYPOCRETIN - DESCRIPTION (provided by applicant): In work first reported in 2000 and supported entirely by the current grant, we identified the cause of human narcolepsy as a loss of cells containing hypocretin (Hcrt, or orexin). Similar results were reported by the group at Stanford University at the same time. While these discoveries have been a major advance in our understanding of narcolepsy, important questions remain unanswered. Despite the discovery of a link between Hcrt cell loss and narcolepsy, the anatomical bases of several major symptoms of narcolepsy remain unexplained. For example, narcoleptics have disrupted nighttime sleep and an increased incidence of REM sleep behavior disorder, symptoms that appear to be opposite to the sleepiness and cataplexy that are the best known characteristics of narcolepsy. It is likely that other brain systems are altered in narcolepsy either by the process that removes Hcrt cells or by the direct and indirect postsynaptic effects of the loss of these cells. We will look for anatomical clues to the changes occurring in narcolepsy by measuring, in Hcrt KO mice and in human narcoleptics, Hcrt receptor numbers and in the number, size, dendritic fields and morphology of cholinergic, monoaminergic and other cells normally receiving Hcrt axonal projections. We will determine which of these changes can be reversed by Hcrt administration to Hcrt knockout mice. Changes in Hcrt receptors and in the structure of the cells receiving Hcrt projections will determine the effect of Hcrt administration as a treatment for narcolepsy. It is unclear whether narcolepsy without cataplexy is the same disease as narcolepsy with cataplexy. Up to half of all narcoleptics diagnosed according to current nosology do not have cataplexy and have normal levels of Hcrt in the cerebrospinal fluid. We will determine the number, distribution and morphology of Hcrt neurons in these patients. Narcolepsy appears to be the simplest neurodegenerative disease, in terms of the very restricted pathology that seems to underlie it. Analysis of how the loss of only 60,000 Hcrt cells causes the varied symptoms of narcolepsy by altering brain anatomy may well serve as a model for comprehending the symptoms of, and developing treatments for, other neurodegenerative diseases, including Parkinson's disease, which we have recently shown is also accompanied by a loss of Hcrt neurons. PUBLIC HEALTH RELEVANCE This work may help clarify the nature of the processes that cause Hcrt cell loss in narcolepsy. It will also help us better understand the sleep symptoms of narcolepsy and may have general relevance for understanding symptoms that are common in narcolepsy, but that are not restricted to narcoleptics, including depression, daytime sleepiness, insomnia and REM sleep behavior disorder.


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: 2013 ( Subtotal = $267,724 )
2013	2013	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	31	11/21/2012	NON-COMPETING CONTINUATION	$249,691
2013	2013	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	31	5/20/2013	NON-COMPETING CONTINUATION	$18,033
														Subtotal = $267,724

Issue Date FY: 2012 ( Subtotal = $277,434 )
2012	2012	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	30	1/31/2012	NON-COMPETING CONTINUATION	$27,743
2012	2012	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	30	11/18/2011	NON-COMPETING CONTINUATION	$249,691
														Subtotal = $277,434

Issue Date FY: 2011 ( Subtotal = $277,434 )
2011	2011	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	12/9/2010	NON-COMPETING CONTINUATION	$254,786
2011	2011	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	29	6/7/2011	NON-COMPETING CONTINUATION	$22,648
														Subtotal = $277,434

Issue Date FY: 2010 ( Subtotal = $280,265 )
2010	2010	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	28	1/20/2010	NON-COMPETING CONTINUATION	$25,479
2010	2010	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	11/20/2009	NON-COMPETING CONTINUATION	$254,786
														Subtotal = $280,265

Issue Date FY: 2009 ( Subtotal = $290,621 )
2009	2009	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	3/13/2009	COMPETING CONTINUATION	$290,621
														Subtotal = $290,621

Issue Date FY: 1998 ( Subtotal = $159,929 )
1998	1998	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biological Basis Research in the Neurosciences	000	19	3/27/1998	NON-COMPETING CONTINUATION	$159,929
														Subtotal = $159,929

Grand Total All Awards = $1,553,407

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NEUROPATHOLOGY OF HYPOCRETIN

Award Number: R01NS014610

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/1983

PERIOD OF PERFORMANCE END DATE: 12/31/2014

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