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

Jansen 干骺端软骨发育不良的 PTH 受体选择性抑制剂的鉴定

• 批准号: 10575154
• 负责人: Juan Manuel Taboas
• 金额: $ 23.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575154
• 关键词: Alleles; Animal Testing; Binding; Biochemical; Biological Assay; Biomedical Engineering; Bone remodeling; Cell Line; Cell Surface Receptors; Cells; Chemistry; Chondrogenesis; Chronic; Clinical; Collaborations; Coupled; Critical Pathways; Cyclic AMP; Defect; Deformity; Development; Disease; Dysplasia; Engineering; Fibrocartilages; Fluorescence Resonance Energy Transfer; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Histologic; Hypercalcemia; Hypophosphatemia; Impairment; In Vitro; Joints; Laboratories; Ligands; Mesenchymal; Mesenchymal Stem Cells; Metaphyseal chondrodysplasia; Methods; Micrognathism; Morphogenesis; Mus; Mutation; Optics; Oral; Organic Chemistry; Osteoblasts; Osteoclasts; Osteogenesis; PTH gene; Palate; Parathyroid Hormone Receptor; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Process; Production; Property; Proteins; Reagent; Receptor Activation; Receptor Cell; Receptor Signaling; Research; Science; Series; Signal Transduction; Skeleton; TMD treatment; Temporomandibular Joint; Testing; Therapeutic; Time; Transgenic Mice; Wild Type Mouse; analytical method; base; bone; computational pipelines; constitutive active receptor; cortical bone; craniofacial; craniofacial development; drug candidate; efficacy testing; functional group; improved; in vivo; inhibitor; interdisciplinary approach; mu receptors; mutant; network models; osteoclastogenesis; parathyroid hormone-related protein; progenitor; programs; receptor; scaffold; simulation; skeletal dysplasia; small molecule; stem cells; theories; translational research program

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.

概括 该项目的目标是测试和优化我们最近发现的小非肽分子（重新 被称为 Pitt 分子）以恢复正常的甲状旁腺激素 1 型受体 (PTHR) 信号和细胞 颞下颌关节 (TMJ) 髁形态发生过程，其表达细胞有缺陷 组成型活性受体突变体引起 詹森干骺端软骨发育不良（JMC）。基于现有 PI 之间的合作（药理学和化学生物学系 Vilardaga 博士和口腔系 Taboas 博士） 和颅面科学，以及生物工程）和co-I （Wipf，化学系）在皮特大学，一个跨学科 已开发出初步方法来证明 Pitt 分子在恢复正常 PTHR 方面的功效 体外信号传导和细胞形态发生过程，从而更好地了解 PTHR 信号的影响 naling 对髁突形态发生的影响。 我们提出 2 个目标： 目标 1 将确定最有效的变构小分子来阻断本构型 使用最先进的光学分析表达 PTHR mu- 的活细胞中的受体信号传导来激活 PTHR JMC 患者（PTHR-H223R、PTHR-T410P 或 PTHR-I458R）中遇到的问题以及药物化学 优化皮特分子阻断特性的方法。目标 2 将更进一步，确定 ef- 生物化学和组织学研究小分子对颞下颌关节髁形态发生的影响 对由野生型和小鼠的髁突间充质祖细胞组成的工程化微组织进行测定 表达 JMC 突变体 PTHR-H223R。 该研究项目的意义在于其前提是更好地了解 PTHR 信号传导的影响 髁突形态发生，并为未来的转化研究计划奠定基础，该计划检查 这些皮特分子在治疗颞下颌疾病方面的治疗效用。