# Targeting the GDF15-GFRAL system to treat nausea and emesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $670,069

## Abstract

Summary
 The growth differentiation factor 15 (GDF15), formerly known as macrophage inhibitory cytokine-1 (MIC-1),
is a cytokine that shows expression and serum rise in response to many conditions and diseases, including
pregnancy, obesity, diabetes, and cancer. GDF15 signaling has gained significant attention in recent years with
multiple papers in 2017 identifying the GDNF family receptor α-like ( GFRAL ) receptor as binding GDF15
selectivelyand with high affinity. However, the reported restrictive expression of the GFRAL receptor to the
area postrema (AP) and nucleus tractus solitarius (NTS) of the brainstem, areas highly critical to both energy
balance and emesis/nausea/malaise suggests that GDF15-GFRAL signaling could be an important factor not only
in long-term body weight regulation, but also in short-term processing of emesis and illness. Behavior. Thus,
understanding what role GDF15-GFRAL signaling plays in illness behavior and anorexia is paramount to
determining the mechanism of GDF15 action. Compelling evidence links GDF15 signaling with chemotherapy-
induced nausea and anorexia, which remain important clinical problems despite relatively well-controlled
chemotherapy-induced emesis, by showing that: 1) GDF15 signaling causes nausea and emesis; 2) an AP/NTS
site of action is responsible for mediating the feeding effects of GDF15 signaling through binding of the GFRAL-
RET receptor complex, and 3) obesity, cancer, and chemotherapy increase circulating GDF15 in rodents and
humans. We hypothesize that a functional dynamic change in the expression of central GDF15 levels in the NTS
and AP will occur following energy balance dysregulation and/or administration of emetic stimuli, and that we
can mitigate/treat such through the unique molecular and behavioral assays and patented peptide-based
technology employed here (i.e. our
peptide-based
inhibitor
bind
nausea
novel GFRAL-RET antagonist “GRASP”). The GRASP antagonist is a small,
sequence with our in vivo and conformational binding models supporting it to be an allosteric
to the GFRAL-RET complex. We have also shown that GRASP can penetrate into the brainstem and
to GFRAL-expressing neurons in the AP/NTS, and consequently attenuate GDF15- and cisplatin-induced
behaviors in rats.To further explore the GDF15-GFRAL system, we propose complimentary studies by a
multi-PI team of established investigators with extensive collaborative experience to investigate the following
aims: Aim I will characterize brainstem circuitry and unbiased single cell transcriptomics for endogenous GDF15
production and GFRAL/RET-expressing neuronal phenotypes. Aim II will characterize GDF15-induced emesis,
nausea behavior, and anorexia as well as characterize the GRASP lead compound against these behaviors with a
multi-species approach. Aim III will characterize the critical mechanistic and stability parameters of GRASP
through rational design of analogs based on functional, computational and structural data to build u...

## Key facts

- **NIH application ID:** 10463832
- **Project number:** 5R01DK130239-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Bart C DE JONGHE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $670,069
- **Award type:** 5
- **Project period:** 2021-08-09 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463832

## Citation

> US National Institutes of Health, RePORTER application 10463832, Targeting the GDF15-GFRAL system to treat nausea and emesis (5R01DK130239-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10463832. Licensed CC0.

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