# The role of cell surface glycosaminoglycans (GAGs) in PTHrP bias signaling

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

Project Summary/Abstract
The parathyroid hormone (PTH)-related protein (PTHrP) is essential for mammary gland development, placental
calcium ion transport, tooth eruption, bone formation and remodeling, and causes hypercalcemia in patients with
malignancy. Our current understanding of how endogenous PTHrP (PTHrP1-141) transduces signals through the
PTH type 1 receptor (PTHR), a Class B G-protein coupled receptor (GPCR), is largely based on studies done
with its N-terminal fragment (PTHrP1-36). However, pilot studies revealed that signaling properties of endogenous
PTHrP are distinct from its N-terminal fragment and dependent on heparin/heparan sulfate, a glycosaminoglycan
(GAG). The role of extracellular matrix components, such as GAGs, in PTHR signaling and trafficking has largely
been ignored. Thus, the goal of this proposal is to determine the molecular and cellular mechanisms by which
heparan sulfate controls PTHrP signaling via PTHR. We hypothesize that the interaction between
heparin/heparan sulfate and PTHrP maintains local concentrations of the hormone at the cell surface, which
enhances the rate of receptor binding and ligand residence time on PTHR, and consequently contributes to
location biased signaling mediated by PTHrP. The first Aim will address this hypothesis by characterizing the
binding properties of PTHrP and heparin/heparan sulfate interaction using biophysical approaches. The second
Aim will employ single-cell and single-molecule optical imaging approaches to determine the functional role of
heparin/heparan sulfate and the mechanism by which PTHrP signals via PTHR. The findings of this proposal will
provide insight into the ligand biased signaling mechanism of PTHR, and contribute to the overall understanding
of GPCR signaling beyond the field of pharmacology.

## Key facts

- **NIH application ID:** 10822295
- **Project number:** 1F31DK136222-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sofya Savransky
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10822295

## Citation

> US National Institutes of Health, RePORTER application 10822295, The role of cell surface glycosaminoglycans (GAGs) in PTHrP bias signaling (1F31DK136222-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10822295. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*