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Posttranslational Regulation of Cell Growth and Stress Responses

Award Number: R35GM134883
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Posttranslational Regulation of Cell Growth and Stress Responses - Project Summary A central goal in disease biology is to describe the molecular processes responsible for transformation of a cell from a normal state into a pathological one. Compared to the rapid progresses in DNA and RNA sequencing technologies, characterization of the final and arguably most actionable element of the central dogma, protein, has lagged behind. The dynamic relationship between the genome of a cell and its proteome is poorly understood, reflecting multiple layers of transcriptional/post-transcriptional regulation. In particular, the complexity of the human proteome is greatly expanded by the ~400 different types of protein posttranslational modifications (PTMs). The various PTM events, either alone or in combination (i.e., “cross-talk”), represent powerful mechanisms to modulate the function of a protein (e.g., activity, stability and localization), the collection of which convey information within the signaling network that underlies the complex traits in various pathophysiological conditions. However, because of many inherent technical difficulties associated with the analysis of protein PTMs (e.g., chemically diverse, unstable and low abundance), a complete description of the posttranslationally modified proteome of any given cells remains a daunting task. The overarching mission of our program is to: (1) develop cutting-edge quantitative proteomic approaches to systematically identify and characterize novel PTMs, (2) comprehensively interrogate the signaling events regulated by phosphorylation (mTOR pathways) and ADP-ribosylation (PARP pathways), and (3) combine these systems biology approaches with classical biochemical, cell biology and animal experiments to decipher the molecular underpinnings of cell growth and stress responses that are controlled by these two important pathways. To accomplish these goals, we will leverage our preliminary results (including a large set of unique hits, reagents and methods), and center our efforts on the following six goals. First, we will develop innovative mass spectrometric technologies with dramatically improved performance for global, quantitative and site-specific analysis of novel PTMs. Second, we will investigate the role of IGFBP5 (a recently identified extracellular target of mTORC1) as a mediator of the “non-cell autonomous” function of mTORC1. Third, we will determine the role of EGR1 (a novel hit identified from our previous MS screen) as a master regulator of the mTORC1-dependent feedback loops. Fourth, we will generate a tissue-specific atlas of mTORC1 phosphorylation substrates, and in doing so, interrogate non-uniform effects of this important pathway on the physiology of different tissues. Fifth, we will develop a large-scale MS approach to site-specific characterization of the D/E-mono-ADP-ribosylated proteome, and finally we will develop a large-scale method to measure absolute protein PARylation stoichiometries. Together, these studies provide a comprehensive framework for the MS identification and functional characterization of PTMs events linked to cell growth control and stress responses.


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 = -$1 )
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	5	8/26/2025	NON-COMPETING CONTINUATION	-$1
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $559,136 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	5	6/28/2024	NON-COMPETING CONTINUATION	$55,914
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	000	5	4/22/2024	NON-COMPETING CONTINUATION	$503,222
														Subtotal = $559,136

Issue Date FY: 2023 ( Subtotal = $559,136 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	002	4	4/11/2023	NON-COMPETING CONTINUATION	$559,136
2023	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	3	11/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$20,777
2023	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	11/21/2022	NON-COMPETING CONTINUATION	-$20,777
														Subtotal = $559,136

Issue Date FY: 2022 ( Subtotal = $559,136 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Biomedical Research and Research Training	001	3	8/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$559,136
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	8/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $559,136

Issue Date FY: 2021 ( Subtotal = $556,870 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	4/22/2021	NON-COMPETING CONTINUATION	$556,870
														Subtotal = $556,870

Issue Date FY: 2020 ( Subtotal = $421,951 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	4/24/2020	NEW	$421,951
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	1	4/29/2020	NEW	$0
														Subtotal = $421,951

Grand Total All Awards = $2,656,228

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Posttranslational Regulation of Cell Growth and Stress Responses

Award Number: R35GM134883

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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