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Unraveling molecular and system-level mechanisms of human disease-associated protein mutations

Award Number: R35GM124952
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: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Unraveling molecular and system-level mechanisms of human disease-associated protein mutations - Project Summary Quickly growing genomic and phenotypic data in large-scale biobank efforts are increasingly associating genetic variants to the predisposition, onset, and progression of human diseases. However, knowledge remains limited about the mechanisms underlying those associations, not to mention that many more variants are with uncertain clinical significance. The widening gap between variant data and mechanistic knowledge further hinders the delivery of prognostics, diagnostics, and therapeutics for growing healthcare demands. In response to the knowledge gap, the PI’s long-term research goal is twofold: (1) to unravel how a genetic change ripples through various aspects across atomic, molecular, and cellular levels to cause human diseases or confer drug resistance; and (2) to translate learned mechanistic knowledge to effective therapeutic strategies for human diseases and drug resistance. Toward the long-term research goal, this project focuses on coding variants leading to protein mutations, builds upon our recent progress in physics-driven protein design and data-driven machine learning for mutational effects, and proposes to widen and deepen the unraveling of disease-associated protein mutations along three directions. The first two directions involve forward prediction and causal inference of hierarchical mutational phenotypes across molecular and cellular levels, which will generate mechanistic hypotheses while predicting disease phenotypes. The third direction involves inverse design of perturbation experiments, including protein mutagenesis and ligand perturbation, to test the generated mechanistic hypotheses directly and rationally. To advance along the three directions in the next five years, we will integrate molecular physics, systems knowledge, and emerging large-scale functional data in a systematic and rigorous framework to probabilistically predict, explain, and design phenotypes of protein mutations across biological scales. And we will fuse molecular modeling, network analysis, multimodal machine learning, graph learning, and conditional generative models in this regard, while continuing experimental and clinical collaborations in teams and communities. The expected contributions of the project, besides the computational methods, predicted phenotypes, hypothesized mechanisms, and designed experiments, also include an integrated data platform friendly for cross-disciplinary machine learning and a resource and discovery platform promoting clinical feedback loops.


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 = $396,002 )
2025	2025	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	002	7	8/20/2025	NON-COMPETING CONTINUATION	$396,002
2025	2024	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
2025	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	5	4/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $396,002

Issue Date FY: 2024 ( Subtotal = $392,641 )
2024	2024	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	6	8/19/2024	COMPETING CONTINUATION	$392,641
														Subtotal = $392,641

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	5	8/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $335,245 )
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	5	8/18/2021	NON-COMPETING CONTINUATION	$335,245
														Subtotal = $335,245

Issue Date FY: 2020 ( Subtotal = $335,245 )
2020	2020	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	4	9/14/2020	NON-COMPETING CONTINUATION	$335,245
														Subtotal = $335,245

Issue Date FY: 2019 ( Subtotal = $335,245 )
2019	2019	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	3	9/4/2019	NON-COMPETING CONTINUATION	$335,245
														Subtotal = $335,245

Issue Date FY: 2018 ( Subtotal = $335,245 )
2018	2018	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	2	8/31/2018	NON-COMPETING CONTINUATION	$335,245
														Subtotal = $335,245

Issue Date FY: 2017 ( Subtotal = $335,245 )
2017	2017	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/12/2017	NEW	$335,245
														Subtotal = $335,245

Grand Total All Awards = $2,464,868

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Unraveling molecular and system-level mechanisms of human disease-associated protein mutations

Award Number: R35GM124952

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: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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