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

• 批准号: 8594689
• 负责人: Marc Nathan Wein
• 金额: $ 5.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594689
• 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

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（由申请人提供）：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，PTH（1-34，Teriparatide）的每日重组形式是唯一经FDA批准的合成代谢骨质疏松症治疗。迄今为止，我们尚未完全了解Teriparatide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信号传导对于Teriparatide刺激净骨产生的能力可能至关重要。硬化蛋白是骨细胞衍生的骨形成的抑制剂，其表达被PTH下调。硬化蛋白是骨质疏松症的新型药物靶标，PTH抑制硬化症可能是Teriparatide治疗效果的重要机制。该建议旨在研究分子机制，从而使骨细胞中的PTH信号传导导致硬化蛋白下调。我们的假设是IIA类组蛋白脱乙酰基酶（HDAC）蛋白在PTH受体和硬化蛋白抑制之间的途径中起着至关重要的作用。我们计划使用体外和体内方法的组合研究IIA HDAC类在该途径中的作用。首先，使用shRNA介导的基因沉默在新型骨细胞细胞系中使用SHRNA介导的基因沉默来操纵IIA类HDAC的水平，该细胞系显示强大的PTH依赖性硬化蛋白的下调。接下来，将进行详细的机械研究，以了解IIA类HDAC类在从PTH到硬化蛋白下调的途径中的功能。最后，将研究缺乏骨细胞IIA HDAC类的小鼠，以确定PTH是否需要IIA类HDAC来降低体内硬化蛋白水平。这些研究将提供有关teriparatide骨代谢效应的骨细胞信号传导途径的关键数据。此外，对这些途径的改进理解可能会导致骨质疏松症的新型疗法的发展。