# Identification of selective inhibitors of PTH-receptor for Jansen’s metaphyseal chondrodysplasia

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $236,435

## Abstract

Summary
The objective of this project is to test and optimize our recently identified small non-peptidic molecules (re-
ferred to as Pitt molecules) to restore normal parathyroid hormone type 1 receptor (PTHR) signaling and cellu-
lar temporomandibular joint (TMJ) condylar morphogenic processes, which are defective in cells expressing
constitutive active receptor mutants causing
Jansen’s metaphyseal chondrodysplasia (JMC). Based on existing
collaborations between PIs (Dr. Vilardaga, Dept. of Pharmacology & Chem. Biol., and Dr. Taboas, Dept. Oral
and Craniofacial Sciences, and of Bioengineering) and co-I
(Wipf, Dept. of Chemistry) at U.Pitt, an interdisci-
plinary approach has been developed to demonstrate the efficacy of Pitt molecules in restoring normal PTHR
signaling and cellular morphogenic processes in vitro, and thereby better understand the effects of PTHR sig-
naling on condylar morphogenesis.
We propose 2 aims: Aim 1 will identify the most effective allosteric small molecules for blocking constitutive
PTHR activation using state-of-the-art optical analysis of receptor signaling in live cells expressing PTHR mu-
tants encountered in JMC patients (PTHR-H223R, PTHR-T410P, or PTHR-I458R), and medicinal chemistry
methods to optimize blocking properties of Pitt molecules. Aim 2 will take a step further by determining the ef-
fect of small molecules on temporomandibular joint condylar morphogenesis using biochemical and histological
assays on engineered microtissues composed of condylar mesenchymal progenitors from wild-type and mice
expressing the JMC mutant PTHR-H223R.
The significance of this research program lies in its premise to better understand the effects of PTHR signaling
on condylar morphogenesis and lay the groundwork for a future translational research program that examines
the therapeutic utility of these Pitt molecules for treatment of temporomandibular disorders.

## Key facts

- **NIH application ID:** 10575154
- **Project number:** 1R21DE032478-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Juan Manuel Taboas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,435
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10575154

## Citation

> US National Institutes of Health, RePORTER application 10575154, Identification of selective inhibitors of PTH-receptor for Jansen’s metaphyseal chondrodysplasia (1R21DE032478-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10575154. Licensed CC0.

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