The role of class II histone deacetylases in PTH signaling in osteocytes

II 类组蛋白脱乙酰酶在骨细胞 PTH 信号传导中的作用

基本信息

批准号：
8715350
负责人：
Marc Nathan Wein
金额：
$ 4.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715350
关键词：
Acetylation Acetyltransferase Cell Line Data Development Down-Regulation Drug Design Drug Targeting Drug usage FDA approved Family Family member G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Expression Gene Silencing Genes Goals Grant HDAC4 gene HDAC5 gene Histone Deacetylase Histones Hormone Responsive Hormones Human In Vitro Knowledge Lead Lysine Mediating Molecular Mus N-terminal New Agents Osteoblasts Osteocytes Osteogenesis Osteoporosis Parathyroid Hormone Receptor Parathyroid Hormone Receptors Parathyroid gland Pathway interactions Pattern Phosphorylation Physiological Play Post-Translational Protein Processing Production Proteins Recombinants Research Role Signal Pathway Signal Transduction Teriparatide Work base bone bone cell calcium metabolism extracellular genome wide association study improved in vivo inhibitor/antagonist myocyte-specific enhancer-binding factor 2 novel peptide hormone protein protein interaction public health relevance small hairpin RNA transcription factor treatment effect

项目摘要

DESCRIPTION (provided by applicant): Parathyroid hormone (PTH) is a peptide hormone with a major role in calcium metabolism. In addition, a daily recombinant form of PTH (1-34, teriparatide) is the only FDA-approved anabolic osteoporosis treatment. To date, we do not fully understand the detailed cellular and molecular mechanism of teriparatide's anabolic effect. PTH receptors are expressed in osteocytes, and PTH signaling in osteocytes is likely to be vital for the ability of teriparatide to stimulate net bone production. Sclerostin is an osteocyte-derived inhibitor of bone formation by osteoblasts whose expression is down-regulated by PTH. Sclerostin is a novel drug target for osteoporosis, and sclerostin inhibition by PTH is likely to b an important mechanism underlying the teriparatide treatment effect. This proposal aims to study the molecular mechanisms whereby PTH signaling in osteocytes leads to sclerostin down-regulation. Our hypothesis is that class IIa histone deacetylase (HDAC) proteins play an essential role in the pathway between the PTH receptor and sclerostin inhibition. We plan to study the role of class IIa HDACs in this pathway using a combination of in vitro and in vivo approaches. First, levels of class IIa HDACs will be manipulated using shRNA-mediated gene silencing in a novel osteocytes cell line which displays robust PTH-dependent sclerostin down-regulation. Next, detailed mechanistic studies will be performed to understand how class IIa HDACs function in the pathway leading from PTH to sclerostin down-regulation. Finally, mice lacking class IIa HDACs in osteocytes will be studied to determine if class IIa HDACs are required for PTH to reduce sclerostin levels in vivo. These studies will provide key data regarding the signaling pathways in osteocytes underlying teriparatide's osteoanabolic effect. In addition, an improved understanding of these pathways may lead to the development of novel therapies for osteoporosis.

描述（申请人提供）：甲状旁腺激素（PTH）是一种肽激素，在钙代谢中起主要作用。此外，每日重组 PTH（1-34，特立帕肽）是 FDA 批准的唯一合成代谢性骨质疏松症治疗方法。迄今为止，我们尚未完全了解特立帕肽合成代谢作用的详细细胞和分子机制。 PTH 受体在骨细胞中表达，骨细胞中的 PTH 信号传导可能对于特立帕肽刺激净骨生成的能力至关重要。 Sclerostin 是一种骨细胞衍生的成骨细胞骨形成抑制剂，其表达受 PTH 下调。硬化素是骨质疏松症的新型药物靶点，PTH 抑制硬化素可能是特立帕肽治疗效果的重要机制。该提案旨在研究骨细胞中 PTH 信号传导导致硬化蛋白下调的分子机制。我们的假设是 IIa 类组蛋白脱乙酰酶 (HDAC) 蛋白在 PTH 受体和硬化素抑制之间的通路中发挥重要作用。我们计划结合体外和体内方法研究 IIa 类 HDAC 在此通路中的作用。首先，将在新型骨细胞系中使用 shRNA 介导的基因沉默来操纵 IIa 类 HDAC 的水平，该细胞系表现出强大的 PTH 依赖性硬化蛋白下调。接下来，将进行详细的机制研究，以了解 IIa 类 HDAC 在从 PTH 到硬化蛋白下调的途径中如何发挥作用。最后，将研究骨细胞中缺乏 IIa 类 HDAC 的小鼠，以确定 PTH 是否需要 IIa 类 HDAC 来降低体内硬化素水平。这些研究将提供有关特立帕肽骨合成代谢作用背后的骨细胞信号传导途径的关键数据。此外，对这些途径的进一步了解可能会导致骨质疏松症新疗法的开发。