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Unlocking sequence-structure-function-disease relationships in large protein super-families

Award Number: R35GM139656
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Unlocking sequence-structure-function-disease relationships in large protein super-families - Project Summary Predicting disease phenotypes from genotypes is a grand challenge in biology and personalized medicine. Our long-term goal is to address this challenge using a combination of computational and experimental approaches. Working towards this goal, we have developed and deployed a powerful evolutionary systems approach to map the complex relationships connecting sequence, structure, function, regulation and disease in biomedically important protein super-families such as protein kinases. We have made important contributions describing the unique modes of allosteric regulation in various protein kinases, deciphering the structural basis of oncogenic activation in a subset of receptor tyrosine kinases, uncovering the regulation of pseudokinases, and developing new tools and resources for addressing data integration challenges in the signaling field. We propose to build on these impactful studies to answer key questions emanating from our ongoing studies such as: What are the functions of pseudokinases, the catalytically-inert members of the kinome, and how can we use pseudokinases to better predict and characterize non-catalytic functions of kinases? What are the functions of conserved cysteine residues in regulatory sites of protein and small molecule kinases and are they post-translationally modified in redox signaling and oxidative stress response that are causally associated with age-related disorders? How can we enhance existing computational models for predicting genome-phenome relationships using structural information, and can machine learning on structurally enhanced knowledge graphs reveal new relationships between patient-derived mutations and disease phenotypes? We propose to answer these questions using a variety of approaches including statistical mining of large sequence datasets, molecular dynamics simulations, machine learning, mass spectrometry, biochemical analysis and in vivo assays. Completion of this work is expected to reveal new allosteric sites for targeting pseudokinase and kinase non-catalytic functions in diseases, and significantly advance our understanding of kinase regulatory mechanisms in disease and normal states. Our work will create new tools and resources for knowledge graph mining and provide explainable models for inferring causal relationships linking genomes and phenomes with potential applications in personalized medicine. Finally, the scope and impact of our work will be significantly broadened by participation in studies extending our specialized tools and technological approaches developed for the study of kinases to other biomedically important gene families such as glycosyltransferases and sulfotransferases.


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 = $415,854 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	001	5	3/4/2025	NON-COMPETING CONTINUATION	$415,854
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	4	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $415,854

Issue Date FY: 2024 ( Subtotal = $462,060 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	001	4	6/20/2024	NON-COMPETING CONTINUATION	$46,206
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	4	1/23/2024	NON-COMPETING CONTINUATION	$415,854
														Subtotal = $462,060

Issue Date FY: 2023 ( Subtotal = $581,968 )
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	002	3	7/13/2023	SUPPLEMENT FOR EXPANSION	$137,650
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	001	3	2/27/2023	NON-COMPETING CONTINUATION	$44,432
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	3	1/9/2023	NON-COMPETING CONTINUATION	$399,886
														Subtotal = $581,968

Issue Date FY: 2022 ( Subtotal = $305,775 )
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	001	2	6/27/2022	NON-COMPETING CONTINUATION	$30,578
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	2	1/19/2022	NON-COMPETING CONTINUATION	$275,197
														Subtotal = $305,775

Issue Date FY: 2021 ( Subtotal = $357,769 )
2021	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	1	1/29/2021	NEW	$357,769
														Subtotal = $357,769

Grand Total All Awards = $2,123,426

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Unlocking sequence-structure-function-disease relationships in large protein super-families

Award Number: R35GM139656

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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