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Regulation by mTORC1 of the lysosomal efflux of essential amino acids

Award Number: F30CA236179
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Regulation by mTORC1 of the lysosomal efflux of essential amino acids - Project Summary/Abstract The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase which coordinates cell growth and metabolism by balancing anabolic and catabolic processes in response to nutrients, growth factor signaling, and energy levels 1,2. Deregulated signaling in this pathway has been implicated in many human diseases including neurodegeneration, diabetes, and cancer3. As such, the mechanisms involved in mTORC1 activation and the biological processes under the control of mTORC1 are of significant interest. Lysosomes play a crucial role in the signal transduction of the nutrient sensing branch of the mTORC1 pathway9. While developing a novel tool for the rapid isolation of pure lysosomes, we made the surprising discovery that mTORC1 regulates the lysosomal concentration of a distinct set of non-polar, mostly essential amino acids. Using the same method, we noticed that loss of SLC38A9, a largely unstudied amino acid transporter that senses lysosomal arginine, results in the accumulation of the same set of non-polar, mostly essential amino acids. Despite this knowledge, the mechanism by which mTORC1 regulates the lysosomal abundance of essential amino acids through SLC38A9 is not known. Elucidation of this mechanism will give key insights into how mammalian cells respond to nutrient availability and may also provide novel therapeutic targets for the treatment of tumors. Preliminary evidence suggests the Rag-Ragulator complex, which interacts with SLC38A9 and conveys the availability of nutrients to mTORC1, is necessary for mTORC1 to regulate the efflux of essential amino acids from lysosomes. To characterize the molecular mechanism by which mTORC1 regulates SLC38A9 transport function, we propose the following aims: . 1. Determine the role of mTORC1 in controlling the interaction between SLC38A9 and Rag- Ragulator. 2. Understand the role of Rag-Ragulator phosphorylation on the regulation of the transport function of SLC38A9. 3. Identification of lysosomal proteins that regulate SLC38A9.


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 = -$18,109 )
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	6	5/22/2024	NON-COMPETING CONTINUATION	$0
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	6	4/18/2024	NON-COMPETING CONTINUATION	-$18,109
														Subtotal = -$18,109

Issue Date FY: 2023 ( Subtotal = $46,897 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	6	11/28/2022	NON-COMPETING CONTINUATION	$51,752
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	002	6	5/22/2023	NON-COMPETING CONTINUATION	$942
2023	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	3	11/23/2022	NON-COMPETING CONTINUATION	-$5,797
														Subtotal = $46,897

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	5	6/1/2022	NON-COMPETING CONTINUATION	$716
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	5	12/3/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	3	11/27/2020	NON-COMPETING CONTINUATION	$50,520
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	002	3	7/30/2021	NON-COMPETING CONTINUATION	-$12,715
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	3	2/2/2021	NON-COMPETING CONTINUATION	$516
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	003	4	7/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,715
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	2	12/23/2019	NON-COMPETING CONTINUATION	$50,016
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	2	3/11/2020	NON-COMPETING CONTINUATION	$504
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	1	11/23/2018	NEW	$28,524
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	002	1	11/30/2018	NEW	$0
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	001	1	11/30/2018	NEW	$21,492
														Subtotal = $50,016

Grand Total All Awards = $232,112

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Regulation by mTORC1 of the lysosomal efflux of essential amino acids

Award Number: F30CA236179

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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