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Dissection of SARM1-Induced Axon Degeneration and Cell Death

Award Number: R01NS087632
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: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Dissection of SARM1-Induced Axon Degeneration and Cell Death - Project Summary/Abstract Programmed axon degeneration (AxD), a.k.a. Wallerian degeneration, is a genetically encoded cellular program akin to apoptosis by which neurons effect the orderly demolition of diseased or damaged axons. Our prior work demonstrated that the chief executioner of AxD, SARM1, is an NAD+ hydrolase allosterically regulated by NAD+ and its precursor NMN. SARM1 activation causes depletion of NAD+ that leads to local metabolic catastrophe and axon dissolution. SARM1-dependent AxD was primarily elucidated in models of acute injury that trigger all-or-none rapid axon loss, but we and others have also identified diverse conditions that provoke chronic SARM1 activation below the threshold necessary to provoke rapid AxD. Such subliminal SARM1 activity likely contributes to common neurodegenerative diseases including ALS, CMT2A and diabetic neuropathy. Our evidence indicates that this activity involves upstream and downstream molecular mechanisms that may not be engaged during canonical axotomy-induced Wallerian degeneration, mechanisms that impair axon resilience and contribute to compromised axon integrity and function in progressive neurodegenerative disorders. To enable the study of this subliminal SARM1 activity, we developed means to both manipulate and monitor the AxD pathway via titrating SARM1 activation and quantitatively measuring cADPR, a SARM1 activity biomarker. Here we use these tools to investigate the regulation of SARM1 by post-translational modification and the mechanisms by which DNA damage induces SARM1-dependent AxD. Our preliminary data show that SARM1 binds to and is ubiquitinated by Parkin in response to mitochondrial damage. We propose experiments to determine the unexplored impact of K63 regulatory ubiquitination on SARM1 activity. Such regulatory events are likely to impact chronic SARM1 activation and progressive disease. We will use kinase inhibitor panels to identify novel SARM1 regulators and employ a fluorescent SARM1 activity sensor and imaging-based screening technologies we recently developed to identify molecular components regulating SARM1 function by performing a CRISPR screen in models of subliminal SARM1 activation using gRNAs targeting all druggable genes including most kinases. We also find that disrupted cellular DNA repair activates SARM1-dependent AxD. DNA damage is associated with peripheral neuropathy in many neurodegenerative diseases including ALS and rare genetic disorders, as well as after chemotherapy. We will define the mechanisms of SARM1 activation due to DNA damage and how SARM1 promotes DNA damage-induced degeneration using human motor neuron models of ALS. Finally, our previous work led directly to development of therapeutic SARM1 inhibitors that are now in clinical development. Here we propose to develop therapeutic SARM1 activators as axon-specific neurolytics to treat localized chronic pain. In total, these studies will define mechanisms that regulate subliminal SARM1 activation relevant to chronic disease, identify alternative therapeutic targets for neurodegenerative disorders, and directly generate novel non-opioid medicines to treat pain.


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 = $603,990 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	6/11/2025	NON-COMPETING CONTINUATION	$603,990
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	3/3/2025	COMPETING CONTINUATION	$16,425
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/3/2025	NON-COMPETING CONTINUATION	-$16,425
														Subtotal = $603,990

Issue Date FY: 2024 ( Subtotal = $566,796 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	8/9/2024	COMPETING CONTINUATION	$566,796
														Subtotal = $566,796

Issue Date FY: 2023 ( Subtotal = $598,620 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/7/2023	NON-COMPETING CONTINUATION	$598,620
														Subtotal = $598,620

Issue Date FY: 2022 ( Subtotal = $598,620 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/3/2022	NON-COMPETING CONTINUATION	$598,620
														Subtotal = $598,620

Issue Date FY: 2021 ( Subtotal = $598,620 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	6/11/2021	NON-COMPETING CONTINUATION	$598,620
														Subtotal = $598,620

Issue Date FY: 2020 ( Subtotal = $552,223 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	6/18/2020	NON-COMPETING CONTINUATION	$552,223
2020	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/8/2020	COMPETING CONTINUATION	$6,486
2020	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/8/2020	NON-COMPETING CONTINUATION	-$6,486
														Subtotal = $552,223

Issue Date FY: 2019 ( Subtotal = $508,832 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/5/2019	COMPETING CONTINUATION	$508,832
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	7/17/2019	COMPETING CONTINUATION	$0
														Subtotal = $508,832

Issue Date FY: 2018 ( Subtotal = $364,634 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/8/2018	NON-COMPETING CONTINUATION	$364,634
														Subtotal = $364,634

Issue Date FY: 2017 ( Subtotal = $364,634 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	6/13/2017	NON-COMPETING CONTINUATION	$36,464
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/26/2017	NON-COMPETING CONTINUATION	$328,170
														Subtotal = $364,634

Issue Date FY: 2016 ( Subtotal = $364,634 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/22/2016	NON-COMPETING CONTINUATION	$364,634
														Subtotal = $364,634

Issue Date FY: 2015 ( Subtotal = $364,634 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/23/2015	NON-COMPETING CONTINUATION	$364,634
														Subtotal = $364,634

Issue Date FY: 2014 ( Subtotal = $352,052 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/18/2014	NEW	$352,052
														Subtotal = $352,052

Grand Total All Awards = $5,838,289

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Dissection of SARM1-Induced Axon Degeneration and Cell Death

Award Number: R01NS087632

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: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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