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Investigations of proteome turnover kinetics under cellular differentiation

Award Number: R35GM146815
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: 09/17/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Investigations of proteome turnover kinetics under cellular differentiation - PROJECT SUMMARY Investigations of Proteome Turnover Kinetics Under Cellular Differentiation: Proteins are in a constant flux of continuous synthesis and degradation, both of which contribute to regulate protein levels in the cell. Although this fact has been known for 80 years, currently most biological inquiries are limited to static snapshots of overall transcript and protein levels, whereas knowledge into the dynamic changes of protein turnover remains severely lagging. This ESI MIRA proposal seeks to advance the current understanding of how cellular proteomes remodel during cell state transitions, by incorporating protein turnover kinetics information at key stages of human induced pluripotent stem cell (iPSC) differentiation into distinct cellular lineages. Working with collaborators, we previously developed deuterium stable isotope labeling, mass spectrometry, and kinetic modeling methods to quantitate protein turnover in animal models and in human. In doing so, we found many novel cell states and disease markers may be discovered from integrating orthogonal protein abundance and kinetics information. In the next five years, we propose to: (1) apply these methods to acquire a high temporal density map of human iPSC trilineage differentiation into cardiomyocyte, hepatocyte, and neuroprogenitor cells; (2) interrogate the regulatory principles that govern turnover flux across different differentiation stages; and (3) assess the functional consequences of protein degradation on the success and cell maturity of terminal cell production. Finally, a limitation of current techniques is that the kinetic models used in protein turnover studies largely assume a non-changing protein pool size at steady state, which does not apply to differentiating cells or progressing diseases. We propose to expand current models of analyzing heavy water stable isotope label experiments toward dynamical systems with variable protein pool sizes. If successful, the proposed research would greatly expand the current knowledge of molecular events that take place during human iPSC differentiation, as well as generate publicly available data sets and software tools to advance protein turnover studies in diverse areas.


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 = $509,187 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	3	12/11/2024	SUPPLEMENT FOR EXPANSION	$48,175
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	4	9/2/2025	NON-COMPETING CONTINUATION	$388,750
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	002	4	9/4/2025	SUPPLEMENT FOR EXPANSION	$72,262
														Subtotal = $509,187

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	3	7/31/2024	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $400,088 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	2	7/26/2023	NON-COMPETING CONTINUATION	$388,750
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	1	5/24/2023	SUPPLEMENT FOR EXPANSION	$11,338
														Subtotal = $400,088

Issue Date FY: 2022 ( Subtotal = $388,750 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	1	9/16/2022	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $1,686,775

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Investigations of proteome turnover kinetics under cellular differentiation

Award Number: R35GM146815

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: 09/17/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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