Pharmacological rescue of tooth eruption disorders

牙萌出障碍的药理学救援

基本信息

批准号：
10737289
负责人：
Wanida Ono
金额：
$ 48.63万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737289
关键词：
3-Dimensional Adjuvant Therapy Affect Alleles Cell Line Cells Clinical Clinical Trials Cyclic AMP Cyclic AMP Receptor Protein Cyclic AMP-Dependent Protein Kinases Dental Sac Dentition Disease Failure Foundations Future Gene Deletion Genetic Genetic Diseases Goals Histologic Human Injections LoxP-flanked allele Malignant Neoplasms Modality Mus Nuclear Translocation Orthodontic Osteoblasts Osteogenesis Osteogenesis Imperfecta Outcome Pathway interactions Patients Phenotype Quality of life Receptor Signaling Reporter Role Signal Induction Signal Pathway Signal Transduction Signaling Protein Structure Tamoxifen Testing Time Tooth eruption Tooth root structure Tooth structure Zoledronic Acid alveolar bone autocrine bisphosphonate bone bone mass clinical application dentin matrix protein 1 functional restoration in vivo innovation kinase inhibitor microCT mouse model mutant novel novel therapeutic intervention novel therapeutics parathyroid hormone-related protein pediatric patients pharmacologic protein expression receptor response salt-inducible kinase skeletal small molecule therapeutic target transcriptome sequencing transcriptomics

项目摘要

Project Summary / Abstract A healthy dentition with appropriately functioning teeth is essential for maintaining quality of life (QOL). Disorders involving tooth eruption are prevalent, as high as 2–4% in permanent molars alone. Multiple molars are involved in severe cases such as rare genetic conditions of primary failure of tooth eruption (PFE) or, more commonly, bisphosphonate-induced arrest of tooth eruption in pediatric patients, which significantly compromise the patients' ability to chew effectively. Because these molars do not response well to conventional orthodontic approaches, innovative adjuvant therapies are needed to restore tooth eruption of affected molars for better clinical outcomes. Tooth eruption is regulated by cells in the dental follicle (DF) surrounding developing molars, which express parathyroid hormone-related protein (PTHrP) and its cognate PTH/PTHrP receptor (PTH1R). Disruption of autocrine PTHrP-PTH1R signaling in PTHrP+ DF cells causes failure of tooth eruption in murine molars that closely recapitulates the human PFE condition. Salt inducible kinases (SIKs) are an essential downstream effector of PTH1R-cAMP/PKA signaling in bone, in which cAMP- regulated PKA-dependent SIK inhibition is a key component of the anabolic actions of PTH. Small molecules SIK inhibitors hold promise as a novel therapeutic strategy to enhance cAMP-induced signals in a receptor- independent manner. In this proposal, we hypothesize that activation of the PTH1R signaling pathway by direct SIK inhibition can restore defective tooth eruption of molars in mouse models of genetically and pharmacologically induced tooth eruption disorders. In Aim 1, we will identify the roles of SIKs in PTHrP+ dental follicle cells in tooth eruption. We hypothesize that SIKs regulate osteoblast cell fates of PTHrP+ DF cells and tooth eruption. We will define the function of SIK2/SIK3 by conditionally deleting these genes in PTHrP+ DF cells at the onset of tooth eruption. We will define short-term and long-term alterations in tooth eruption and tooth root structures of mutant molars using histological and 3D microCT analyses. In Aim 2, we will determine the effects of SIK inhibition in rescuing PFE in molars. We hypothesize that SIK inhibition rescues failure of tooth eruption in molars genetically caused by PTH1R deficiency. We will determine the effects of SIK inhibition in a mouse model of PFE, in which PTH1R is conditionally deleted in PTHrP+ DF cells at the onset of tooth eruption. We will investigate whether PFE phenotypes can be rescued genetically by a concomitant loss of SIK2/SIK3, and pharmacologically by SIK inhibitor YKL-05-099. In Aim 3, we will define PTHrP as a bisphosphonate target and effects of SIK inhibitors in rescuing tooth eruption. We hypothesize that PTHrP- PTH1R signaling is altered in PTHrP+ DF cells in response to zoledronic acid (ZOL), and ZOL-induced arrest of tooth eruption in molars can be rescued by SIK inhibitors. We will treat ZOL-treated young mice with YKL-05- 099 to rescue tooth eruption. We will also define how ZOL inhibits PTHrP-PTH1R signaling activities, and whether SIK inhibitors reverse ZOL-induced alternation of PTHrP signaling and aberrant PTHrP+ DF cell fates.

项目概要/摘要健康的牙列和功能正常的牙齿对于维持生活质量 (QOL) 至关重要。涉及牙齿萌出的疾病很普遍，仅恒磨牙的发病率就高达 2-4%。涉及严重病例，例如原发性牙齿萌出失败（PFE）的罕见遗传病或更多通常，双磷酸盐会导致儿童患者的牙齿萌出停止，这显着损害患者有效咀嚼的能力，因为这些臼齿对牙齿的反应不佳。传统的正畸方法，需要创新的辅助疗法来恢复牙齿萌出受影响的磨牙以获得更好的临床结果。牙齿萌出由牙囊 (DF) 中的细胞调节。周围发育中的磨牙，表达甲状旁腺激素相关蛋白（PTHrP）及其同源蛋白 PTH/PTHrP 受体 (PTH1R) 破坏 PTHrP+ DF 细胞中的自分泌 PTHrP-PTH1R 信号传导。小鼠磨牙的牙齿萌出失败，与人类盐诱导的 PFE 状况非常相似。激酶 (SIK) 是骨中 PTH1R-cAMP/PKA 信号传导的重要下游效应器，其中 cAMP- 调节的 PKA 依赖性 SIK 抑制是 PTH 小分子合成代谢作用的关键组成部分。 SIK 抑制剂有望作为一种新的治疗策略，增强受体中 cAMP 诱导的信号在本提案中，我们追求通过直接激活 PTH1R 信号通路。 SIK 抑制可以恢复遗传和遗传因素小鼠模型中磨牙的缺陷牙齿萌出药物诱导的牙齿萌出障碍在目标 1 中，我们将确定 SIK 在 PTHrP+ 牙科中的作用。我们认为 SIK 调节 PTHrP+ DF 细胞的成骨细胞命运。我们将通过有条件地删除 PTHrP+ DF 中的这些基因来定义 SIK2/SIK3 的功能。我们将定义牙齿萌出时的短期和长期变化。在目标 2 中，我们将使用组织学和 3D microCT 分析确定突变磨牙的牙根结构。 SIK 抑制对挽救磨牙 PFE 的影响我们发现 SIK 抑制可挽救失败。遗传性 PTH1R 缺陷导致的磨牙萌出我们将确定 SIK 的影响。 PFE 小鼠模型中的抑制，其中 PTHrP+ DF 细胞中的 PTH1R 在 PFE 开始时被条件性删除我们将研究是否可以通过伴随的牙齿萌出来从基因上挽救 PFE 表型。 SIK2/SIK3，以及 SIK 抑制剂 YKL-05-099 的药理学作用在目标 3 中，我们将 PTHrP 定义为双膦酸盐靶点和 SIK 抑制剂在挽救牙齿萌出中的作用我们突袭了 PTHrP-。 PTHrP+ DF 细胞中的 PTH1R 信号传导因唑来膦酸 (ZOL) 的反应而改变，并且 ZOL 诱导的 SIK 抑制剂可以挽救磨牙的牙齿萌出我们将用 YKL-05- 治疗 ZOL 治疗的幼鼠。 099 拯救牙齿萌出我们还将定义 ZOL 如何抑制 PTHrP-PTH1R 信号活动，以及 SIK 抑制剂是否能逆转 ZOL 诱导的 PTHrP 信号转导和异常 PTHrP+ DF 细胞命运的改变。