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Network-based Framework to Decode Novel Gain-of-Function Mutations and their Mechanistic Roles in General Human Diseases

Award Number: R35GM133658
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Network-based Framework to Decode Novel Gain-of-Function Mutations and their Mechanistic Roles in General Human Diseases - PROJECT SUMMARY The explosion of genomic information has left behind many fundamental questions regarding genotype- phenotype relationships unresolved. Genes and proteins do not function in isolation but interact in cellular networks critical for signal transduction, survival and differentiation. Mechanistic understanding of human disease requires finding and understanding the molecular interactions and biochemical activities that disease- causing mutations perturb. In distinct individuals (with varying genotypes), precise signal transduction controls biological function, including gene regulation and phenotypic output. Wet-lab in vitro and in vivo experimental testing can be time-consuming and expensive, especially when it comes to large-scale efforts. Research in my laboratory is focused on developing and implementing computational and bioinformatic technologies to understand the functional effects of genetic mutations on molecular interaction networks and gene regulatory networks, bridging genotype and phenotype in health and disease. Our overall goal is to contribute to the understanding of disease mechanisms and of more open ended questions about explanations for ‘missing heritability’ in genome-wide association studies. Although computational models/predictions have made substantial progress in functional genomics and have contributed to variants’ prioritization, classification and annotation, several challenges still remain. In the next five years, we will start to address the following key challenges using our innovative methodologies. First, we will accurately predict the impact of mutations on perturbing specific protein interactions by devising a novel sequence-only interaction language model. Second, we will unravel context-specific gene-environment interactions by developing a multimodal structure-based deep learning algorithm. Finally, we will identify essential genetic interactions that govern cell fate as actionable targets for biological engineering, using our transfer learning technology. Our extensive expertise in the field supports the premise of this proposal. Overall this integrative study is innovative because it will provide novel insights in ‘functionalizing’ mutations, yielding patient-specific disease mechanisms at a higher resolution, a critical step towards personalized precision medicine. Furthermore, the proposed research is significant because it will help annotate/characterize the large number of variants of unknown significance (VUS), providing a fundamental link between genotype and phenotype in disease. We envision that it will be instrumental to push current human genetics research paradigm towards a thorough functional and quantitative modeling of all genomic mutations and their interactome and gene regulatory networks involved in disease development and progression. 1


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: 2026 ( Subtotal = $441,375 )
2026	2026	BAYLOR RESEARCH INSTITUTE	3434 LIVE OAK ST	DALLAS	TX	75204	DALLAS	USA	Biomedical Research and Research Training	000	6	3/4/2026	COMPETING CONTINUATION	$441,375
														Subtotal = $441,375

Issue Date FY: 2025 ( Subtotal = -$439,703 )
2025	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	5	4/8/2025	NON-COMPETING CONTINUATION	-$439,703
														Subtotal = -$439,703

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	5	7/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $393,169 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	5	9/13/2023	NON-COMPETING CONTINUATION	$393,169
														Subtotal = $393,169

Issue Date FY: 2022 ( Subtotal = $593,159 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	001	4	8/26/2022	NON-COMPETING CONTINUATION	$393,169
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	3	8/22/2022	SUPPLEMENT FOR EXPANSION	$199,990
														Subtotal = $593,159

Issue Date FY: 2021 ( Subtotal = $393,169 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	3	9/1/2021	NON-COMPETING CONTINUATION	$393,169
														Subtotal = $393,169

Issue Date FY: 2020 ( Subtotal = $393,169 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	2	8/25/2020	NON-COMPETING CONTINUATION	$393,169
														Subtotal = $393,169

Issue Date FY: 2019 ( Subtotal = $371,324 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	1	9/12/2019	NEW	$371,324
														Subtotal = $371,324

Grand Total All Awards = $2,145,663

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Network-based Framework to Decode Novel Gain-of-Function Mutations and their Mechanistic Roles in General Human Diseases

Award Number: R35GM133658

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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