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DEVELOPMENT OF IDENTIFIED MOTONEURONS

Award Number: R01NS023915
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: 07/01/1986
PERIOD OF PERFORMANCE END DATE: 05/31/2013

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DEVELOPMENT OF IDENTIFIED MOTONEURONS - DESCRIPTION (provided by applicant): The ability of animals to move depends on motoneurons sending appropriate signals to muscles. This ability is compromised by spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS). Our long term goal is to use individually identified motoneurons in embryonic zebrafish as a model to understand normal motoneuron development; this knowledge is critical for designing therapies for spinal cord injuries and diseases such as ALS. We hypothesize that transcription factor networks control specific aspects of motoneuron development such as axon morphology, neurotransmitter activity, expression of ion channels and receptors, and survival. We propose a series of experiments to address this hypothesis. Motoneurons do not form in the absence of the Islet1 transcription factor, suggesting that it is a motoneuron master regulator . In zebrafish lacking Islet1, motoneurons develop an interneuron-like morphology, but maintain expression of several motoneuron genes, including transcription factors. These results suggest that Islet1 regulates some but not all aspects of motoneuron differentiation, and thus is not a motoneuron master regulator. We propose that motoneuron development is regulated by transcription factor modules that promote specific motoneuron characteristics and suppress specific interneuron characteristics. To deduce the logic by which transcriptional modules regulate motoneuron development, we propose to knock down expression of specific transcription factors using morpholino oligonucleotides and to examine motoneuron and interneuron markers, including axons, neurotransmitters, receptors, and ion channels. About half of the motoneurons initially formed during vertebrate development die from lack of availability or access to trophic support. We propose that the Notch and Netrin signaling pathways interact during motoneuron development, resulting in limited access of specific zebrafish motoneurons to trophic support and death of these cells. We propose to test this hypothesis by altering Netrin and Notch function. Many genes involved in motoneuron development remain unknown. We propose a microarray screen to discover these genes based on their differential expression. In this screen, we will compare spinal cords of embryos with supernumerary motoneurons to those of embryos lacking motoneurons. Genes isolated in this screen will feed back into the other studies in this proposal. Our ability to study individual zebrafish spinal neurons provides an unprecedented opportunity to learn the mechanisms that regulate motoneuron differentiation and survival. Our proposed studies will provide insights that should facilitate new therapies for treatment of motoneuron diseases and injury. In humans, spinal cord injury and diseases such as amyotrophic lateral sclerosis (ALS) compromise the ability of motoneurons to activate muscle, leading to devastating consequences such as paralysis and death. Our proposed studies will help reveal mechanisms that regulate motoneuron differentiation and survival, thus providing insights that should facilitate new therapies for treatment of motoneuron diseases and injury.


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: 2012 ( Subtotal = $498,286 )
2012	2012	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	6/4/2012	NON-COMPETING CONTINUATION	$498,286
														Subtotal = $498,286

Issue Date FY: 2011 ( Subtotal = $493,518 )
2011	2011	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	6/6/2011	NON-COMPETING CONTINUATION	$493,518
														Subtotal = $493,518

Issue Date FY: 2010 ( Subtotal = $494,000 )
2010	2010	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	23	6/21/2010	NON-COMPETING CONTINUATION	$494,000
2010	2009	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	4/29/2010	NON-COMPETING CONTINUATION	$0
2010	2008	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	4/27/2010	COMPETING CONTINUATION	$0
														Subtotal = $494,000

Issue Date FY: 2009 ( Subtotal = $542,018 )
2009	2009	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	8/27/2009	SUPPLEMENT FOR EXPANSION	$64,464
2009	2009	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	5/21/2009	NON-COMPETING CONTINUATION	$477,554
														Subtotal = $542,018

Issue Date FY: 2008 ( Subtotal = $548,680 )
2008	2008	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	2/21/2008	COMPETING CONTINUATION	$523,680
2008	2008	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	9/5/2008	SUPPLEMENT FOR EXPANSION	$25,000
														Subtotal = $548,680

Issue Date FY: 2006 ( Subtotal = $415,762 )
2006	2006	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	3/22/2006	NON-COMPETING CONTINUATION	$415,762
														Subtotal = $415,762

Issue Date FY: 2005 ( Subtotal = $413,360 )
2005	2005	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	3/14/2005	NON-COMPETING CONTINUATION	$413,360
														Subtotal = $413,360

Issue Date FY: 2004 ( Subtotal = $421,325 )
2004	2004	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	4/15/2004	SUPPLEMENT FOR EXPANSION	$20,000
2004	2004	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	4/5/2004	NON-COMPETING CONTINUATION	$401,325
														Subtotal = $421,325

Issue Date FY: 2003 ( Subtotal = $389,635 )
2003	2003	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17		NON-COMPETING CONTINUATION	$389,635
														Subtotal = $389,635

Issue Date FY: 2002 ( Subtotal = $478,226 )
2002	2002	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	3/30/2002	COMPETING CONTINUATION	$478,226
														Subtotal = $478,226

Issue Date FY: 2000 ( Subtotal = $285,306 )
2000	2000	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biological Basis Research in the Neurosciences	000	15	8/19/2000	NON-COMPETING CONTINUATION	$285,306
														Subtotal = $285,306

Issue Date FY: 1999 ( Subtotal = $274,464 )
1999	1999	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biological Basis Research in the Neurosciences	000	14	5/18/1999	NON-COMPETING CONTINUATION	$274,464
														Subtotal = $274,464

Issue Date FY: 1998 ( Subtotal = $323,387 )
1998	1998	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biological Basis Research in the Neurosciences	000	13	4/23/1998	NON-COMPETING CONTINUATION	$277,254
1998	1998	UNIVERSITY OF OREGON	5215 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biological Basis Research in the Neurosciences	001	13	9/2/1998	SUPPLEMENT FOR EXPANSION	$46,133
														Subtotal = $323,387

Grand Total All Awards = $5,577,967

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DEVELOPMENT OF IDENTIFIED MOTONEURONS

Award Number: R01NS023915

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: 07/01/1986

PERIOD OF PERFORMANCE END DATE: 05/31/2013

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