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

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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.