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Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD

Award Number: R01NS112503
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD - Cytoplasmic protein accumulations of the RNA/DNA binding protein TDP-43 are found in affected neurons in almost all instances of amyotrophic lateral sclerosis (ALS) and approximately 50% of frontotemporal dementia (FTD). Nuclear clearance of TDP-43 has been widely observed in affected neurons in sporadic ALS/FTD, evidence strongly supporting the proposal that TDP-43 loss of function is a key aspect of disease mechanism underlying ALS/FTD pathogenesis. We have identified that the mRNA encoding stathmin-2 is 1) an essential factor for axonal regeneration of axotomized iPSC-derived motor neurons and 2) the mRNA most affected by reduction in TDP-43 function, with a striking loss from motor neurons in sporadic ALS and inherited disease from GGGGCC expansion in C9orf72. Stathmin-2 is an abundant, direct binding partner of α/β-tubulin dimers in neuronal perikarya, axons, growth cones, and synapses, including neuromuscular junctions (NMJs). Using genome editing, we will identify the mechanism of TDP-43-dependent premature polyadenylation/cryptic splicing that suppresses stathmin-2 synthesis when TDP-43 levels are lowered. We will use genome editing of induced pluripotent stem cells (iPSCs) derived human motor neurons grown in compartmented chambers (that separate neuronal cell bodies, axons and growth cones) to determine how stathmin-2 functions in a) motor neuron maintenance/repair, b) axonal microtubule stabilization and/or dynamics, c) neuromuscular junction formation and/or stabilization, and d) how palmitoylation of stathmin-2 affects its axonal function(s). Genome wide CRISPR/Cas9 screens using flow cytometry and optical methods will be undertaken to identify factors that control stathmin-2 synthesis or accumulation. Finally, we will determine the consequences in mice of reduction or loss of stathmin-2 on motor neuron function and muscle innervation/denervation and whether reduction in stathmin-2 synergizes with TDP-43 mutation to drive motor neuron disease. Outcomes of these efforts will provide key insights for understanding basic aspects of axonal and synaptic neurobiology and for evaluating whether maintaining or restoring stathmin-2 is an attractive therapeutic option in sporadic ALS/FTD and ALS from its most frequent genetic cause, repeat expansion in C9orf72.


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: 2024 ( Subtotal = $839,174 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/24/2024	NON-COMPETING CONTINUATION	$839,174
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	8/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $839,174

Issue Date FY: 2023 ( Subtotal = $853,797 )
2023	2023	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	7/13/2023	NON-COMPETING CONTINUATION	-$797,070
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	7/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$853,797
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	5	9/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$509,195
2023	2023	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/14/2023	NON-COMPETING CONTINUATION	$797,070
2023	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/11/2023	NON-COMPETING CONTINUATION	$0
2023	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	9/15/2023	NON-COMPETING CONTINUATION	-$509,195
														Subtotal = $853,797

Issue Date FY: 2022 ( Subtotal = $797,269 )
2022	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/1/2022	NON-COMPETING CONTINUATION	$797,269
2022	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $797,269

Issue Date FY: 2021 ( Subtotal = $798,489 )
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/11/2021	NON-COMPETING CONTINUATION	$0
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/11/2021	NON-COMPETING CONTINUATION	$798,489
														Subtotal = $798,489

Issue Date FY: 2020 ( Subtotal = $826,652 )
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/12/2020	NEW	$139,927
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/18/2020	NEW	$686,725
														Subtotal = $826,652

Grand Total All Awards = $4,115,381

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Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD

Award Number: R01NS112503

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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