# Modulating Metabolic Gene Expression with Small Molecule Agonists for LRH-1

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $54,279

## Abstract

Project Summary/Abstract
Liver homolog receptor (LRH-1) is a nuclear receptor that plays a key role in hepatic metabolic signaling.
Targeting LRH-1 in the context of obesity results in marked improvements in insulin sensitivity and hepatic lipid
homeostasis. This suggests that LRH-1 could be an important therapeutic target in metabolic diseases such as
Type 2 diabetes and fatty liver disease.
Using structure-based design, novel LRH-1 modulators have been developed that potently activate LRH-1 both
in vitro and in vivo. However, it remains unknown how activating LRH-1 with synthetic agonists will modulate
gene expression and metabolic signaling pathways. In Aim 1, RNA-seq and ChIP-seq methods will be used to
examine how synthetic agonists with different binding mechanisms can alternately regulate LRH-1 target
genes in primary human hepatocytes. In Aim 2, diet-induced obese mice will be dosed with a synthetic LRH-1
agonist to treat their metabolic dysfunction. Parameters of lipid and glucose homeostasis will be measured to
elucidate the effectiveness of an LRH-1 agonist in reversing metabolic symptoms. To ensure agonist specificity
for LRH-1, LRH-1 KO mice will be used as experimental controls. As one of the first studies to target LRH-1 in
vivo with synthetic agonists, this research will provide vital information about the therapeutic potential of
targeting LRH-1 to treat metabolic diseases.
Fellowship training will be conducted in the departments of Biochemistry and Surgery at Emory University
School of Medicine and will include hands-on training in transcriptomic sequencing, lipidomics, and mouse
transgenics and physiology. Training will take place in the stimulating intellectual environment at Emory
University and draw upon the expertise of several collaborators and research cores. The IRACDA Fellowships
in Research and Science Teaching (FIRST) program and the Office of Postdoctoral Education will also provide
additional teaching and professional development opportunities. In summary, the pioneering research
described here in combination with the exceptional training environment will ensure the successful
development of this applicant into an independent research investigator.

## Key facts

- **NIH application ID:** 9911759
- **Project number:** 1F32DK120195-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Elizabeth Joy Millings
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,279
- **Award type:** 1
- **Project period:** 2020-04-01 → 2021-01-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911759

## Citation

> US National Institutes of Health, RePORTER application 9911759, Modulating Metabolic Gene Expression with Small Molecule Agonists for LRH-1 (1F32DK120195-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9911759. Licensed CC0.

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