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Digital twins of the hypothalamus, placenta, and GI for the therapeutics of gestational diabetes

Award Number: OT2OD042825
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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Digital twins of the hypothalamus, placenta, and GI for the therapeutics of gestational diabetes - This project aims at characterizing the excitability and metabolic adaptation of hypothalamic neuronal circuitry integrated with placental hormones and glucose-insulin regulation in the GI during pregnancy. During pregnancy, physiologic adaptive strategies assure the availability of nutrients for the oUspring’s growth and health. Increased caloric intake, body fat accrual, and altered glucose homeostasis are coordinated by a complex neuronal network modulated by circulating hormones and metabolic cues. Among them, placental hormones, leptin, and insulin are critical players. Transient leptin and insulin resistance have physiologic roles during gestation, allowing for energy accumulation in fat tissue and glucose availability for fetal growth. Women who are obese are three to four times more likely to develop gestational diabetes (GDM), maternal hypertension, or preeclampsia. The causal factors of excess gestational weight gain and post-pregnancy metabolic syndrome present many unique challenges to rationalizing therapeutic choices. Prior studies illustrate the main players involved in glucose control, including prolactin, agouti-related peptide (AgRP), and leptin. For example, the neuronal circuitry model of the hypothalamus helps to clarify how placental lactogens alter the transcriptome of metabolically relevant neurons projecting to the paraventricular nucleus of the hypothalamus (PVH), thereby regulating melanocortin output. An imbalance in this circuitry disrupts female metabolic ﬂexibility during and after gestation. Knowing this for an individual can provide a justiﬁcation in part for rational therapeutic choices. It is expected that ﬁndings from this project will advance our understanding of physiological adaptations and metabolic ﬂexibility during pregnancy and will provide avenues for clinical research and improvement of women’s health and care. A digital twin can be constructed by combining a mechanistic model with patient-speciﬁc parameter values derived or estimated from patient data. Such an approach enables leveraging known mechanisms of glucose control and beneﬁts from a wealth of data to augment a mechanism-based model. The mechanistic model will be constructed to provide an individualized rationale for therapeutic choices. First, a novel mechanistic model of the hypothalamus, placenta, and the gastrointestinal (GI) tract and a workﬂow will be constructed to generate digital twins for pregnant women enrolled in our study (Aim 1). Next, a virtual population of digital twins will be used to perform simulations to predict diUerences in glucose control due to genetic proﬁle diUerences (Aim 2). Last, therapeutic interventions (drugs, doses, scheduling) will be rationally designed to minimize the events of hyperglycemia and hypoglycemia associated with gestational diabetes (Aim 3). The short-term goal is to reconstruct the integrated digital twins of the computational model in healthy, obese, and type II diabetic cohorts. The long-term goal is to gain insights into therapeutics with the real-time optimal combination therapy of insulin and metformin.


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 = $1,937,392 )
2026	2026	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Trans-NIH Research Support	000	1	9/3/2026	NEW	$1,937,392
														Subtotal = $1,937,392

Grand Total All Awards = $1,937,392

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Digital twins of the hypothalamus, placenta, and GI for the therapeutics of gestational diabetes

Award Number: OT2OD042825

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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