# A porcine model for investigating the role of an insulin signaling regulator in development and disease

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $311,596

## Abstract

ABSTRACT
In humans and domestic animals, the growing fetus undergoes programming of metabolic organs and organelles
to adapt for poor nutrient supply in utero and in anticipation of similar shortage of nutrients postnatally. This
phenomenon known as “Developmental Origins of Health and Disease (DOHaD)” or “thrifty phenotype” is
observed in humans and domestic animals, and manifests as “small for gestation age” (SGA) or “low birth weight”
(LBW) offspring at the time of birth. In humans, the SGA offspring are at high risk for developing obesity, diabetes
and cardiovascular diseases in postnatal life. The LBW piglets on the other hand exhibit reduced feed efficiency,
growth performance and altered carcass characteristics, resulting in great economic losses. Therefore, the study
of DOHaD in a pig model, specifically the Ossabaw pigs that have a naturally occurring thrifty phenotype has the
potential advantage of improving animal health, product quality and profitability in animal agriculture, while
simultaneously serving as a translational model for humans, making it an ideal fit for “Dual-purpose with dual-
benefit” grant program. Using this model, our main goal is to investigate the role of GRB10 (growth hormone
receptor binding protein 10), an adaptor protein and inhibitor of insulin signaling in mediating DOHaD. In humans,
GRB10 is linked to 10% of Silver–Russell syndrome (SRS) cases with severe SGA, and from GWAS studies to
Type II diabetes. In mice, ablation and overexpression experiments have highlighted Grb10 as an antagonist of
insulin signaling, a growth inhibitor, and mediator of metabolic syndrome.
Our Central hypothesis is that altered insulin signaling is key to mediating thrifty phenotype, and modulation of
GRB10 expression will therefore be key to overcoming DOHaD. In this study, using CRISPR/Cas system, GRB10
KO and transgene knockin (KI) Ossabaw fetal fibroblasts were generated. Along with precursor wildtype (WT)
cells, clonal lines of KO, KI, and WT piglets will be generated by somatic cell nuclear transfer. Using this
experimental pipeline, Aim-1 will investigate the effect of ablation and overexpression of GRB10 in prenatal and
postnatal growth. Piglets will be sacrificed at term or after a period of postnatal growth to evaluate the effect of
loss or overexpression of GRB10 on growth rate. Aim-2 will investigate the effect of altered insulin signaling
mediated by GRB10 on metabolic health and fetal programming. We will investigate the loss of GRB10 or
overexpression on the development of obesity and diabetes when fed obesogenic diet. Animals that exhibit
metabolic syndrome will be bred and the offspring investigated for transgenerational inheritance of the
phenotype. We anticipate that the results from the project will validate GRB10 as a regulator of growth-an
agriculturally important trait, and as a candidate for therapeutic intervention of diabetes and metabolic syndrome.

## Key facts

- **NIH application ID:** 10180992
- **Project number:** 5R01HD092304-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Chad Harmon Stahl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $311,596
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180992

## Citation

> US National Institutes of Health, RePORTER application 10180992, A porcine model for investigating the role of an insulin signaling regulator in development and disease (5R01HD092304-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180992. Licensed CC0.

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