Wednesday, December 31, 2025 12/31/2025

Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

Award Number: R01NS084412
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: 12/15/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance - Project Summary Mitochondrial dysfunction and protein homeostasis (proteostasis) failure are common among diverse brain disorders, from neurodegenerative disease and stroke/traumatic brain injury to brain tumor and psychiatric diseases. It is not clear whether these seemingly disparate pathological features are mechanistically interconnected. Mitochondria play important roles in bioenergetics as well as other essential aspects of cellular physiology, such as calcium buffering, intermediary metabolism, and apoptosis. Maintaining mitochondrial quality and quantity is essential for tissue homeostasis, especially the highly energy-demanding neuromuscular tissues. Pten-induced kinase 1 (PINK1) and Parkin (encoding an E3 ubiquitin ligase), two genes associated with familial Parkinson's disease (PD), constitute a genetic pathway important for maintaining mitochondrial health and neuromuscular integrity. Identiﬁcation of this pathway offers a much-needed entry point to decipher the relationship between mitochondrial dysfunction and other pathological hallmarks of disease. Our studies in previous funding cycles revealed that PINK1/Parkin directs an interconnected mitochondrial quality control process important for neuromuscular tissue integrity. This process encompasses biogenesis of respiratory chain, mitochondrial ﬁssion/fusion dynamics, transport, and mitophagy, and is regulated by mechanistic target of rapamycin complexes (mTORC1 and mTORC2). Importantly, in the last funding cycle, we found that ribosome-associated quality control (RQC), a recently recognized protein quality control mechanism that surveys the translating ribosomes for faulty translation products to safeguard proteostasis, is an important player in PINK1/Parkin-directed mitochondrial homeostasis. These new ﬁndings thus provide a mechanistic link between mitochondrial function and cellular proteostasis. We found that a highly conserved RQC factor responds to mitochondrial stress and PINK1 dysfunction and is required for stress adaptation. Activation of this RQC factor effectively rescued PINK1 mutant phenotypes. Moreover, our preliminary studies identiﬁed several upstream factors that regulate the post-translational modiﬁcation (PTM) of this RQC factor. These results laid the foundation for understanding the normal physiological function of this key RQC factor and the upstream signaling mechanisms that regulate its activity in RQC and cellular homeostasis. We will use a powerful combination of molecular genetics, genomics, cell biology, and biochemistry approaches, and move between in vivo ﬂy models, mouse models, and human iPSC-derived cell culture models to seek common mechanisms. We will test the hypothesis that this RQC factor directs the quality control of the translation of mitochondrial outer membrane-associated cytosolic mRNAs to promote mitochondria and neuromuscular tissue homeostasis under stress, and that it provides a signaling node for integrating diverse upstream regulatory inputs to ensure the efﬁciency and ﬁdelity of this translation process.


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: 2026 ( Subtotal = $498,123 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	12/12/2025	NON-COMPETING CONTINUATION	$498,123
														Subtotal = $498,123

Issue Date FY: 2025 ( Subtotal = $553,658 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	1/16/2025	COMPETING CONTINUATION	-$63
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	12/4/2024	COMPETING CONTINUATION	$553,721
														Subtotal = $553,658

Issue Date FY: 2024 ( Subtotal = -$195 )
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/27/2024	NON-COMPETING CONTINUATION	-$195
														Subtotal = -$195

Issue Date FY: 2023 ( Subtotal = $342,344 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/14/2023	NON-COMPETING CONTINUATION	$342,344
														Subtotal = $342,344

Issue Date FY: 2022 ( Subtotal = $342,344 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/25/2022	NON-COMPETING CONTINUATION	$342,344
														Subtotal = $342,344

Issue Date FY: 2021 ( Subtotal = $687,833 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/1/2021	NON-COMPETING CONTINUATION	$342,344
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/14/2021	SUPPLEMENT FOR EXPANSION	$345,489
														Subtotal = $687,833

Issue Date FY: 2020 ( Subtotal = $342,344 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/14/2020	NON-COMPETING CONTINUATION	$342,344
														Subtotal = $342,344

Issue Date FY: 2019 ( Subtotal = $342,344 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/29/2019	COMPETING CONTINUATION	$342,344
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	7/10/2019	COMPETING CONTINUATION	$26
2019	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/22/2019	NON-COMPETING CONTINUATION	$0
2019	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	7/10/2019	NON-COMPETING CONTINUATION	-$26
														Subtotal = $342,344

Issue Date FY: 2018 ( Subtotal = $351,094 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/25/2018	NON-COMPETING CONTINUATION	$35,110
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/24/2017	NON-COMPETING CONTINUATION	$315,984
														Subtotal = $351,094

Issue Date FY: 2017 ( Subtotal = $351,094 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	6/19/2017	NON-COMPETING CONTINUATION	$35,110
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/5/2016	NON-COMPETING CONTINUATION	$315,984
														Subtotal = $351,094

Issue Date FY: 2016 ( Subtotal = $315,984 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/18/2015	NON-COMPETING CONTINUATION	$315,984
														Subtotal = $315,984

Issue Date FY: 2015 ( Subtotal = $351,094 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/5/2015	NON-COMPETING CONTINUATION	$35,110
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/22/2014	NON-COMPETING CONTINUATION	$315,984
														Subtotal = $351,094

Issue Date FY: 2014 ( Subtotal = $351,094 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/9/2013	NEW	$351,094
														Subtotal = $351,094

Grand Total All Awards = $4,829,155

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Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

Award Number: R01NS084412

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: 12/15/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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