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Molecular and genetic studies of NMNAT2 in neuroprotection

Award Number: R01NS086794
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: 09/15/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Molecular and genetic studies of NMNAT2 in neuroprotection - PROJECT SUMMARY / ABSTRACT The high and increasing prevalence as well as the staggering social and financial costs of Alzheimer’s Disease (AD) and AD-related dementia (ADRD) emphasize the importance of finding strategies to prevent or slow their progression. Here we aim to elucidate the basic biology of neuronal maintenance and energy homeostasis to enable us to design new therapeutic strategies independent of tau or beta-amyloid theories. Almost all neurons are born early in life and require an active neuroprotection program for their survival in response to the myriad of internal and external challenges they face throughout life. NMNAT2 is a bifunctional protein that we and others have identified as an important neuronal maintenance factor. NMNAT2 synthesizes nicotinamide mononucleotide (NAD+) and serves as a molecular chaperone for day-to-day axonal function and to protect neurons from proteinopathies such as hyperphosphorylated tau. In AD patients, NMNAT2 abundance is greatly reduced to less than 50% of normal level and its level correlates with cognitive function. We found that deleting NMNAT2 from mouse cortical glutamatergic neurons results in AD/ADRD-like phenotypes, such as glucose hypometabolism, axonopathy and neuroinflammation. The current mouse and human results strongly support a causal relationship between NMNAT2 hypofunction and neurodegeneration. Axonal degeneration is a key step in AD/ADRD and many neurodegenerative diseases. Axonal transport plays critical roles in neuronal function and survival and is extremely energy demanding. Abnormal axonal transport is an early defect in axons destined to degenerate. Increasing evidence reveals dysregulated glucose metabolism in AD. Our preliminary studies suggest that NMNAT2 plays a critical role in fast axonal transport by maintaining axonal energy homeostasis. Deleting NMNAT2 in glutamatergic neurons reduces glycolysis while at the same time augmenting the pentose phosphate. These findings raise the following questions: Does NMNAT2 in glutamatergic neurons play essential roles in maintaining energy homeostasis for normal axonal function? Does glucose hypometabolism caused by loss of NMNAT2 cause axonopathy? Will supplement strategies bypassing NMNAT2 support neurons and attenuate axonopathy? To answer these questions, we propose the following aims: 1. Test the hypothesis that NMNAT2 is required in cortical neurons for axonal transport. 2. Test the hypothesis that NMNAT2 contributes to axonal energy homeostasis. 3. Test the hypothesis that NMNAT2 in cortical neurons is essential for glucose metabolism The knowledge gained from our proposed studies will help us gain mechanistic understanding into how NMNAT2 contributes to active neuronal maintenance and will provide necessary insights to assist in drug discovery using NMNAT2 as a therapeutic target for neurodegeneration.


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: 2025 ( Subtotal = $462,158 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	3/26/2025	NON-COMPETING CONTINUATION	$462,158
														Subtotal = $462,158

Issue Date FY: 2024 ( Subtotal = $564,004 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	3/13/2024	SUPPLEMENT FOR EXPANSION	$56,835
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/11/2024	NON-COMPETING CONTINUATION	$456,453
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	10	8/5/2024	NON-COMPETING CONTINUATION	$50,716
														Subtotal = $564,004

Issue Date FY: 2023 ( Subtotal = $569,268 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/23/2023	NON-COMPETING CONTINUATION	$512,710
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	3/25/2023	SUPPLEMENT FOR EXPANSION	$56,558
														Subtotal = $569,268

Issue Date FY: 2022 ( Subtotal = $660,909 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	2/25/2022	NON-COMPETING CONTINUATION	$532,218
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	4/1/2022	NON-COMPETING CONTINUATION	$59,138
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	3/14/2022	SUPPLEMENT FOR EXPANSION	$69,553
														Subtotal = $660,909

Issue Date FY: 2021 ( Subtotal = $563,912 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	5/15/2021	COMPETING CONTINUATION	$2,026
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/25/2021	COMPETING CONTINUATION	$563,912
2021	2019	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/15/2021	SUPPLEMENT FOR EXPANSION	-$2,026
														Subtotal = $563,912

Issue Date FY: 2019 ( Subtotal = $50,000 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	BRYAN HALL 107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/7/2019	SUPPLEMENT FOR EXPANSION	$50,000
														Subtotal = $50,000

Issue Date FY: 2018 ( Subtotal = $406,293 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	BRYAN HALL 107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/20/2018	NON-COMPETING CONTINUATION	$406,293
														Subtotal = $406,293

Issue Date FY: 2017 ( Subtotal = $421,751 )
2017	2017	TRUSTEES OF INDIANA UNIVERSITY	205C BRYAN HALL, 105 N INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/14/2017	NON-COMPETING CONTINUATION	$421,751
														Subtotal = $421,751

Issue Date FY: 2016 ( Subtotal = $427,201 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/9/2016	NON-COMPETING CONTINUATION	$427,201
														Subtotal = $427,201

Issue Date FY: 2015 ( Subtotal = $423,255 )
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/25/2015	NON-COMPETING CONTINUATION	$424,067
2015	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/8/2015	NEW	-$422,375
2015	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	9/21/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$812
2015	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/9/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$422,375
														Subtotal = $423,255

Issue Date FY: 2014 ( Subtotal = $445,490 )
2014	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/10/2014	NEW	$0
2014	2014	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/3/2014	NEW	$445,490
														Subtotal = $445,490

Grand Total All Awards = $4,994,241

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Molecular and genetic studies of NMNAT2 in neuroprotection

Award Number: R01NS086794

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: 09/15/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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