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Linking tau proteostasis with neuronal activity in FTD

Award Number: U54NS100717
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Linking tau proteostasis with neuronal activity in FTD - ABSTRACT — OVERALL COMPONENT Neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), are characterized by tau inclusions of hyperphosphorylated tau. However, which tau species are pathogenic and how they induce neuronal dysfunction remain elusive. We hypothesize that there is a crosstalk between tau proteostasis imbalance, in the form of intracellular accumulation and intercellular spread, and neuronal dysfunction. Our vision statement is: Linking tau proteostasis with neuronal activity in FTD. We propose to use a combination of unbiased discovery and focused hypothesis- driven approaches to dissect the mechanistic connection. The Center, composed of three projects (P1–P3) and five cores (MS, CRISPR, Human, Data and Admin), aims at addressing the following fundamental questions in tau pathogenesis. In Specific Aim 1, we will address what causes tau to accumulate and spread in FTD. P1 and P3 will work together with MS core to dissect whether aberrant post-translational modifications (PTMs) are critically involved in modulating tau's failure to be degraded and subsequent release. P1, P2 and P3 will work together with CRISPR core to dissect the uptake and seeding mechanisms, using a combination of hypothesis-driven candidate approaches and genome-wide CRISPRi/a library screening. P1, P2 and P3 will work together with the Human core to validate the findings from iPSC neurons in human tissues. In Specific Aim 2, we will determine how tau proteostasis imbalance induces neuronal dysfunction. Despite large amount of evidence supporting the accumulation and spread of tau pathology in animal models and in cultured cells, little is known about the mechanisms behind this toxicity and their direct impact on neuronal/synaptic function in human neurons. P1 and P2 will work together to define the effects of FTD mutations on human neuronal activity both at the single-cell and network levels using whole-cell patch clamp and multi-electrode array (MEA), respectively. P3 will work with P1 and P2 to examine if altered autophagy affects neuronal activity. P1, P2 and the CRISPR core will work together to examine the functional effects of tau oligomerization. In Specific Aim 3, we will examine how neuronal activity modulates tau proteostasis. Both in vitro and in vivo studies showed that the release of tau is activity-dependent, supporting a feedback mechanism by which aberrant neuronal activity further alters tau proteostasis. P1 will work with the MS and CRISPR cores to dissect the mechanisms underlying the activity-dependent tau release. P1 and P2 will work synergistically to address if and how neuronal activity could affect the uptake (P2) or seeding (P1) of pathogenic tau. P3 will work with P1 and P2 to determine how altering neuronal activity modulates different autophagic pathways. In summary, the Center is strategically structured to maximize conceptual and technological synergies, full data integration and cross-validation. We anticipate discovery of novel insights into mechanisms underlying tau toxicity, generation of novel resources and reagents, and development of innovative technology platforms.


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 = -$5,243 )
2024	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/18/2023	NON-COMPETING CONTINUATION	-$5,243
														Subtotal = -$5,243

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	5	8/23/2021	NON-COMPETING CONTINUATION	$0
2021	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	4/16/2021	NON-COMPETING CONTINUATION	$152,259
2021	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	4	8/12/2021	NON-COMPETING CONTINUATION	-$152,259
2021	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	8/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$152,259
2021	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/29/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$151,455
2021	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/29/2021	NON-COMPETING CONTINUATION	$151,455
2021	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	4/16/2021	NON-COMPETING CONTINUATION	-$152,259
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $2,043,639 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/19/2020	NON-COMPETING CONTINUATION	$2,043,639
2020	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,043,639

Issue Date FY: 2019 ( Subtotal = $2,043,636 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	9/24/2019	NON-COMPETING CONTINUATION	$0
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	9/6/2019	NON-COMPETING CONTINUATION	$2,043,636
2019	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	2/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$151,455
2019	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/10/2019	NON-COMPETING CONTINUATION	-$151,455
														Subtotal = $2,043,636

Issue Date FY: 2018 ( Subtotal = $2,212,394 )
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	9/21/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,149,676
2018	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/21/2018	NON-COMPETING CONTINUATION	$0
2018	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/12/2018	NON-COMPETING CONTINUATION	$62,718
														Subtotal = $2,212,394

Issue Date FY: 2017 ( Subtotal = $2,270,177 )
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/12/2017	NON-COMPETING CONTINUATION	$2,255,674
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/29/2017	SUPPLEMENT FOR EXPANSION	$14,503
														Subtotal = $2,270,177

Issue Date FY: 2016 ( Subtotal = $2,255,764 )
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/26/2016	NEW	$2,255,764
														Subtotal = $2,255,764

Grand Total All Awards = $10,820,367

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Linking tau proteostasis with neuronal activity in FTD

Award Number: U54NS100717

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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