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Discovering Chemical Activity Networks-Predicting Bioactivity Based on Structure

Award Number: R35ES031709
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Discovering Chemical Activity Networks-Predicting Bioactivity Based on Structure - PROJECT SUMMARY NIEHS has established Predictive Toxicology as a strategic goal for advancing environmental health sciences. The overarching goal of this RIVER proposal is to predict animal toxicity of chemicals based on their structure. My team and I will expose millions of zebrafish embryos to a library of 10,000 synthetic chemicals across wide concentration ranges. If a chemical shows signs of bioactivity, we will systematically analyze whole animal gene expression changes before the phenotype appears. We will formulate hypotheses about which biomolecular targets the chemicals attacked initially and which pathways led to the observed endpoint. To test those hypotheses, we will edit the zebrafish genome via CRISPR/Cas9 to knock out or over-express critical genes, to discover the ones causally related to the chemical phenotypes. These studies will be highly relevant to human health. Zebrafish possess fully integrated vertebrate organ systems that perform the same functions as their human counterparts and demonstrate well-conserved physiology. Eighty-four percent of the genes that participate in human disease also exist in zebrafish. Zebrafish studies provide a fast, inexpensive way to screen a large volume of chemicals, generate rich hypotheses for drug development, and prioritize candidates for toxicity studies with mammals and human cell cultures. We will compare our results with those of human cell culture studies to clarify the strengths and weaknesses of each method and to reduce the uncertainty associated with applying zebrafish results to human biology. We will post our experimental results in a public database that explains which of the 10,000 Tox21 chemicals are bioactive, which initial targets they strike, and which pathways lead to which endpoints in embryonic and juvenile zebrafish. This information will enable green chemists to detoxify products by substituting a biologically inactive molecule. It will help toxicologists and risk assessors to prioritize chemicals for expensive experiments with rodents and human cell cultures. It will give pharmaceutical scientists thousands of new data points upon which to develop hypotheses about how to modulate a given gene target or activate a given pathway. We will use machine-learning-based chemoinformatic approaches to analyze our zebrafish data and infer the relationship between the structure of a chemical and its biological activity. Our rich data about chemical activity networks will advance the scientific community’s understanding of linkages between chemical exposure and phenotypes. Our work will enable scientists to predict whether a chemical will be biologically active, what target it will act upon, and what networks it will perturb, solely on the basis of its structure. It will enable scientists to reduce, refine, and replace experiments with animals, including zebrafish, and to predict chemical activity networks with computers.


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 = $899,841 )
2025	2025	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	000	5	6/28/2025	NON-COMPETING CONTINUATION	$899,841
														Subtotal = $899,841

Issue Date FY: 2024 ( Subtotal = $924,091 )
2024	2024	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	001	4	5/28/2024	NON-COMPETING CONTINUATION	$924,091
2024	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	000	3	5/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $924,091

Issue Date FY: 2023 ( Subtotal = $856,057 )
2023	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	000	3	6/21/2023	NON-COMPETING CONTINUATION	$856,057
														Subtotal = $856,057

Issue Date FY: 2022 ( Subtotal = $849,950 )
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	000	2	6/15/2022	NON-COMPETING CONTINUATION	$849,950
														Subtotal = $849,950

Issue Date FY: 2021 ( Subtotal = $779,811 )
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Environmental Health	000	1	7/14/2021	NEW	$779,811
														Subtotal = $779,811

Grand Total All Awards = $4,309,750

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Discovering Chemical Activity Networks-Predicting Bioactivity Based on Structure

Award Number: R35ES031709

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/16/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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