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Modeling the hormonal influence on central metabolism: drug off-target prediction and protein synthesis

Award Number: OT2OD042823
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: OTHER
PERIOD OF PERFORMANCE START DATE: 09/14/2026
PERIOD OF PERFORMANCE END DATE: 09/13/2027

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Modeling the hormonal influence on central metabolism: drug off-target prediction and protein synthesis - The overall goal of this project is to develop and experimentally validate a sex- and hormone-informed computational model of cellular metabolism that can predict metabolic behavior, cartilage matrix production, and drug off-target effects using articular chondrocytes as a model system. This tool will be useful for providing mechanistic resolution into how males and females differentially use metabolism to produce specific proteins, as well as how drugs (for example, osteoarthritis (OA)-targeting drugs) may interact with central metabolism to generate unintended off-target effects. This project will expand the current stoichiometric model of central metabolism to include hormonal modulation by estrogen and progesterone, with particular emphasis on osteoarthritis (OA) related to women’s health during menopausal transition. This model will be analyzed with computational infrastructure to be developed in this project that will also be shared with the greater research community. A web-enabled version will be developed to allow users to analyze their own data. This model will be based on experimental studies using primary human male chondrocytes and female chondrocytes from peri- and postmenopausal aged donors. These primary data collection studies will determine both baseline metabolic parameters (e.g. preferred carbon sources, O2 consumption rates, etc.) to define possible sex differences during this age transition, and how metabolism of these cells responds to estrogen and progesterone. Readouts will include targeted and untargeted metabolomic profiles, proteomic profiles, cellular heat production by isothermal microcalorimetry, and measures of matrix synthesis. How these parameters differ by sex, age, and with hormones in chondrocytes is currently unknown. Further experimental studies will expand the targeted library of central metabolites for quantitation from both clinical and laboratory samples. In silico studies will allow dynamic AI-based expansion of the baseline metabolic model to include additional networks based on untargeted metabolomic results. Off-target effects will be analyzed using a novel unified knowledge graph that integrates multiple databases including KEGG, Human-GEM, DrugBank, STITCH, ChEMBL, HMDP, and Rhea. The model will predict key metabolic reactions that result in negative off-target effects. The model will be validated using independent experiments with human chondrocytes. Completion of this project will result in a validated model of sex-dependent metabolism that can predict how cells respond to estrogen and progesterone stimulation as well as predicting synthesis levels of target proteins and drug off target effects. This will be valuable to the greater research community by providing a tool that enables prediction of both specific protein synthesis (e.g. for tissue regeneration) and off-target effects for drug development. Most importantly, this study will reveal currently unknown information about cellular metabolism that can inform the use of hormone therapy in women going through the menopause transition.


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 = $3,385,837 )
2026	2026	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Trans-NIH Research Support	000	1	9/3/2026	NEW	$3,385,837
														Subtotal = $3,385,837

Grand Total All Awards = $3,385,837

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Modeling the hormonal influence on central metabolism: drug off-target prediction and protein synthesis

Award Number: OT2OD042823

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: OTHER

PERIOD OF PERFORMANCE START DATE: 09/14/2026

PERIOD OF PERFORMANCE END DATE: 09/13/2027

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