Wednesday, January 15, 2025 1/15/2025

Disease Mechanism and Therapy in TDP-43 Proteinopathies and Dementias

Award Number: R01NS027036
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Nuclear clearance and cytoplasmic aggregation of TDP-43 have been reported in almost every age-dependent neurodegenerative disease, including as the defining feature of a recently recognized dementia in the oldest of the elderly, an AD-like syndrome named Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), a proportion of the hippocampal neurons in Alzheimer's disease (AD), >40% of frontal temporal dementia (FTD), and >90% of instances of ALS. Our prior efforts (for which we now seek renewed support) have established that transient stress can induce Liquid-Liquid Phase Separation (LLPS) of cytoplasmic TDP-43 into liquid droplets that then transition to a solid state, slowly deplete nuclear TDP-43, and provoke cell death over a timescale of weeks. We also determined that partial or complete proteasome inhibition (to mimic the established decline in proteosome activity during normal aging) provokes TDP-43 mislocalization/accumulation within the cytoplasm. Quantitative mass spectrometry (with proximity-labeling and isobaric-tagging) has identified the small heat shock protein HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and subsequent aggregation. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and mediates disassembly of stress-induced, TDP-43 droplets. Building on our prior and continuing work, we now propose to determine 1) how the age-dependent decrease in proteasome activity drives TDP-43 loss of function, cytoplasmic mislocalization, phase separation, and aggregation and 2) how protein chaperone HSPB1, in conjunction with HSP70, affects cytoplasmic TDP-43 phase separation, inhibits TDP-43 assembly into fibrils, and mediates disassembly of TDP-43 droplets. We have also initiated development of an approach to generate new/replacement neurons in the aged adult mouse brain by transiently suppressing the RNA binding protein Polypyrimidine Tract Binding Protein-1 (PTB) using an antisense oligonucleotide (ASO) delivered by a single injection into cerebral spinal fluid (CSF). Radial glial-like cells (and possibly other GFAP-expressing cells) convert into new neurons over a two month period, acquire mature neuronal character, and functionally integrate into endogenous circuits that modify mouse behavior. Here we will systematically identify the functionality, localization, cell origin, timing, and molecular pathways of cells undergoing identity conversion, with a primary assay the development and utilization of single cell RNA signatures obtained with spatial transcriptomics (Multiplexed Error-Robust Fluorescence In Situ Hybridization [MERFISH]).


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 = $768,106 )
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	37	8/14/2024	NON-COMPETING CONTINUATION	$768,106
														Subtotal = $768,106

Issue Date FY: 2023 ( Subtotal = $773,824 )
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	000	36	8/11/2023	NON-COMPETING CONTINUATION	$773,824
														Subtotal = $773,824

Issue Date FY: 2022 ( Subtotal = $779,544 )
2022	2022	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	35	6/30/2022	COMPETING CONTINUATION	$779,544
														Subtotal = $779,544

Issue Date FY: 2021 ( Subtotal = $647,454 )
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	34	7/28/2021	NON-COMPETING CONTINUATION	$647,454
														Subtotal = $647,454

Issue Date FY: 2020 ( Subtotal = $647,454 )
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	33	8/11/2020	NON-COMPETING CONTINUATION	$647,454
														Subtotal = $647,454

Issue Date FY: 2019 ( Subtotal = $647,454 )
2019	2019	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	32	7/11/2019	NON-COMPETING CONTINUATION	$647,454
														Subtotal = $647,454

Issue Date FY: 2018 ( Subtotal = $647,454 )
2018	2018	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	31	7/25/2018	NON-COMPETING CONTINUATION	$647,454
2018	2016	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	29	2/22/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $647,454

Issue Date FY: 2017 ( Subtotal = $661,854 )
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	30	8/9/2017	COMPETING CONTINUATION	$661,854
2017	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	29	8/10/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	29	1/10/2017	EXTENSION WITH OR WITHOUT FUNDS	$46,112
2017	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	1/10/2017	NON-COMPETING CONTINUATION	-$46,112
														Subtotal = $661,854

Issue Date FY: 2016 ( Subtotal = $492,551 )
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	4/29/2016	EXTENSION WITH OR WITHOUT FUNDS	$492,551
														Subtotal = $492,551

Issue Date FY: 2015 ( Subtotal = $492,551 )
2015	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	5/4/2015	NON-COMPETING CONTINUATION	$492,551
														Subtotal = $492,551

Issue Date FY: 2014 ( Subtotal = $487,625 )
2014	2014	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	27	5/7/2014	NON-COMPETING CONTINUATION	$487,625
														Subtotal = $487,625

Issue Date FY: 2013 ( Subtotal = $475,311 )
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	4/25/2013	NON-COMPETING CONTINUATION	$443,297
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	5/21/2013	NON-COMPETING CONTINUATION	$32,014
														Subtotal = $475,311

Issue Date FY: 2012 ( Subtotal = $492,551 )
2012	2012	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	5/4/2012	COMPETING CONTINUATION	$492,551
														Subtotal = $492,551

Issue Date FY: 2004 ( Subtotal = $575,154 )
2004	2004	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	3/18/2004	NON-COMPETING CONTINUATION	$525,154
2004	2004	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	7/26/2004	SUPPLEMENT FOR EXPANSION	$50,000
														Subtotal = $575,154

Issue Date FY: 2003 ( Subtotal = $509,861 )
2003	2003	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16		NON-COMPETING CONTINUATION	$509,861
														Subtotal = $509,861

Issue Date FY: 2002 ( Subtotal = $495,006 )
2002	2002	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	5/23/2002	NON-COMPETING CONTINUATION	$495,006
														Subtotal = $495,006

Issue Date FY: 2001 ( Subtotal = $358,309 )
2001	2001	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	9/19/2001	COMPETING CONTINUATION	$0
2001	2001	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	9/20/2001	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,309
														Subtotal = $358,309

Issue Date FY: 2000 ( Subtotal = $322,827 )
2000	2000	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biological Basis Research in the Neurosciences	000	12	8/19/2000	NON-COMPETING CONTINUATION	$322,827
														Subtotal = $322,827

Issue Date FY: 1999 ( Subtotal = $310,409 )
1999	1999	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biological Basis Research in the Neurosciences	000	11	4/22/1999	NON-COMPETING CONTINUATION	$310,409
														Subtotal = $310,409

Issue Date FY: 1998 ( Subtotal = $298,470 )
1998	1998	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biological Basis Research in the Neurosciences	000	10	4/29/1998	NON-COMPETING CONTINUATION	$298,470
														Subtotal = $298,470

Grand Total All Awards = $10,883,769

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Disease Mechanism and Therapy in TDP-43 Proteinopathies and Dementias

Award Number: R01NS027036

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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