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Developing Neuroprotective Strategies for Tau and TDP-43 Proteinopathy in FTLD

Award Number: R01NS064131
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: 02/15/2009
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Developing Neuroprotective Strategies for Tau and TDP-43 Proteinopathy in FTLD - Neuronal lesions containing either abnormal pathological tau or abnormal pathological TDP-43 protein characterize frontotemporal lobar degeneration (FTLD). How aggregated, ubiquitinated and phosphorylated TDP-43 protein causes neuronal dysfunction and neurodegeneration is unknown. Likewise, the mechanisms of tau toxicity remain incompletely understood, but hyperphosphorylated, aggregated, and oligomeric tau species exhibit neurotoxicity. This work focuses on extending our previous studies of TDP-43 proteinopathy to complete the molecular genetic dissection of the mechanisms causing neurodegeneration in FTLD-tau and FTLD-TDP. In the previous funding period we showed activation of tau tubulin kinase 1 (TTBK1) stimulates the production of phosphorylated TDP-43, which drives neurodegeneration. We also demonstrated that Calcineurin is the major TDP-43 phosphatase responsible for detoxifying phosphorylated TDP-43. Surprisingly, both TTBK1 and calcineurin play a similar role in the genesis of pathological tau protein in disease. Taken together these findings support the premise of this application that common molecular mechanisms may underpin both TDP-43 and tau pathology in FTLD. The specific aims of this competitive renewal are: 1) Identify genes with protective variants preventing tau or TDP-43 proteinopathy; 2) Conduct comparative analysis of protective genetic variants for impact in molecular mechanisms of neurodegeneration; 3) Assess protective variants for translational potential as therapeutic targets. Completion of the proposed work will enable the development of neuroprotective strategies targeting pathological tau and TDP-43 in FTLD. The experiments proposed here will define new genes and pathways mediating tau and TDP-43 toxicity. The work will also delineate the relationships between the identified genes and pathways to inform development of new therapies for FTLD.


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 = $0 )
2025	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	5/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $549,271 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/23/2022	NON-COMPETING CONTINUATION	$549,271
														Subtotal = $549,271

Issue Date FY: 2021 ( Subtotal = $538,722 )
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	7/5/2021	NON-COMPETING CONTINUATION	$538,722
														Subtotal = $538,722

Issue Date FY: 2020 ( Subtotal = $551,207 )
2020	2020	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	7/1/2020	NON-COMPETING CONTINUATION	$551,207
2020	2019	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	1/27/2020	COMPETING CONTINUATION	$132
2020	2018	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/27/2020	NON-COMPETING CONTINUATION	-$132
														Subtotal = $551,207

Issue Date FY: 2019 ( Subtotal = $568,671 )
2019	2019	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	3/18/2019	COMPETING CONTINUATION	$0
2019	2019	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	3/12/2019	COMPETING CONTINUATION	$568,671
														Subtotal = $568,671

Issue Date FY: 2018 ( Subtotal = $295,313 )
2018	2018	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	9/3/2018	NON-COMPETING CONTINUATION	$295,313
														Subtotal = $295,313

Issue Date FY: 2017 ( Subtotal = $295,313 )
2017	2017	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/17/2017	NON-COMPETING CONTINUATION	$295,313
														Subtotal = $295,313

Issue Date FY: 2016 ( Subtotal = $295,313 )
2016	2016	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/6/2016	NON-COMPETING CONTINUATION	$295,313
														Subtotal = $295,313

Issue Date FY: 2015 ( Subtotal = $295,313 )
2015	2015	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/1/2015	NON-COMPETING CONTINUATION	$295,313
														Subtotal = $295,313

Issue Date FY: 2014 ( Subtotal = $295,313 )
2014	2014	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/3/2014	COMPETING CONTINUATION	$295,313
2014	2013	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/30/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $295,313

Issue Date FY: 2013 ( Subtotal = $252,653 )
2013	2013	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/23/2013	NON-COMPETING CONTINUATION	$17,018
2013	2013	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/8/2013	NON-COMPETING CONTINUATION	$235,635
														Subtotal = $252,653

Issue Date FY: 2012 ( Subtotal = $261,817 )
2012	2012	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/25/2012	NON-COMPETING CONTINUATION	$261,817
														Subtotal = $261,817

Issue Date FY: 2011 ( Subtotal = $261,817 )
2011	2011	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/10/2011	NON-COMPETING CONTINUATION	$21,373
2011	2011	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/21/2011	NON-COMPETING CONTINUATION	$240,444
														Subtotal = $261,817

Issue Date FY: 2010 ( Subtotal = $260,467 )
2010	2010	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/24/2010	NON-COMPETING CONTINUATION	$260,467
														Subtotal = $260,467

Issue Date FY: 2009 ( Subtotal = $254,664 )
2009	2009	SEATTLE INSTITUTE FOR BIOMEDICAL & CLINICAL RESEARCH	1660 SOUTH COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/30/2009	NEW	$254,664
														Subtotal = $254,664

Grand Total All Awards = $4,975,854

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Developing Neuroprotective Strategies for Tau and TDP-43 Proteinopathy in FTLD

Award Number: R01NS064131

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: 02/15/2009

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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