A Neuronal Basis for the Osteocalcin Regulation of Bone Mass

骨钙素调节骨量的神经元基础

基本信息

批准号：
9979842
负责人：
Gerard Karsenty
金额：
$ 38.04万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979842
关键词：
Acetylcholine Address Affect Area Autonomic nervous system Binding Biology Blood - brain barrier anatomy Brain Catecholamines Cells Communities Complex Cues Data Dopamine-beta-monooxygenase Exhibits Extracellular Matrix Face Fostering G-Protein-Coupled Receptors GPRC6A gene Gene Deletion Genes Genetic Epistasis Goals Histologic Hormones Investigation Knockout Mice Knowledge Laboratories Lead Mediating Molecular Molecular Genetics Mus Nervous system structure Neural Crest Cell Neuraxis Neurons Organ Orphan Osteoblasts Osteocalcin Osteogenesis Parasympathetic Nervous System Peripheral Phenotype Physiological Prosencephalon Proteins Recycling Regulation Reporting Research Rest Signal Transduction Skeleton Sympathetic Nervous System Testing Time Tyrosine 3-Monooxygenase bone bone mass craniofacial cranium design experimental study extracellular hormone regulation improved in vivo inhibitor/antagonist interest locus ceruleus structure novel receptor tool

项目摘要

Project Summary The existence of a neuronal control of bone mass has received over the years many confirmations of various kind. Although those are by no means the only example of neuronal control of bone mass, the sympathetic nervous system inhibits bone mass accrual by hampering bone formation whereas the parasympathetic nervous system favors bone mass accrual. However, neuronal of regulation of bone mass accrual has never been explored as a possible means to explore bone mass phenotype caused by the absence of various osteoblast- derived proteins. Likewise, more often than not the importance of neuronal control of bone mass has not been studied in the craniofacial region. This is surprising since many osteoblasts in bones of the skull and face originate from neural crest cells. Osteocalcin is the most abundant non-collagenous protein of the bone extracellular matrix, the absence of which results in a poorly understood high bone mass phenotype. Osteocalcin is also an hormone and in that capacity it favors, following its binding to as novel receptor described in this application, the synthesis of catecholamine in the brain and thereby the activity of the sympathetic nervous system centrally. Independently of this function, as shown in another set of preliminary result of this application, osteocalcin signals through its first receptor described, Cyprc6a, to inhibit the activity of the parasympathetic nervous system. Both types of regulation of the autonomic nervous system by osteocalcin could hamper bone mass accrual. Hence, these preliminary data provide two possible mechanisms to explain what has never been explained until now: the high bone mass phenotype seen in mice lacking osteocalcin. We intend to address this question by studying the regulation of bone mass by osteocalcin in the craniofacial region, as well as in the rest of the skeleton. The Specific Aims of this application are:  To determine whether an inactivation of Gpr158 in the forebrain will result in a high bone mass by decreasing the sympathetic tone.  To determine whether an inactivation of Gprc6a in post-ganglionic parasympathetic neurons will result in a high bone mass phenotype.  To test through rescue and genetic epistasis experiments whether osteocalcin regulation of the sympathetic and/or parasympathetic tone explains its regulation of bone mass accrual.

项目概要多年来，骨量神经控制的存在已得到各种证据的证实。尽管这些绝不是神经控制骨量的唯一例子，但交感神经。神经系统通过阻碍骨形成来抑制骨量增长，而副交感神经系统则通过阻碍骨形成来抑制骨量增长。系统有利于骨量增长然而，骨量增长的神经调节从未被研究过。探索作为探索由于缺乏各种成骨细胞而引起的骨量表型的可能方法同样，神经控制骨量的重要性也常常未被重视。这是在颅面部区域进行的研究，因为头骨和面部的骨骼中有许多成骨细胞。骨钙素源自神经嵴细胞，是骨骼中最丰富的非胶原蛋白。细胞外基质，缺乏细胞外基质会导致人们对高骨量骨钙素表型知之甚少。也是一种激素，在与本文中描述的新受体结合后，它有利于这种能力应用，儿茶酚胺在大脑中的合成，从而影响交感神经的活动独立于该功能的系统，如该应用程序的另一组初步结果所示，骨钙素通过其第一个受体 Cyprc6a 发出信号，抑制副交感神经的活动骨钙素对自主神经系统的两种调节都会损害骨骼。因此，这些初步数据提供了两种可能的机制来解释从未发生过的事情。到目前为止的解释是：在缺乏骨钙素的小鼠中观察到的高骨量表型我们打算解决这个问题。通过研究骨钙素对颅面部及其他部位骨量的调节来回答这个问题该应用程序的具体目标是： - 通过以下方法确定前脑中 Gpr158 的失活是否会导致高骨量降低交感神经张力。 - 确定节后副交感神经元中 Gprc6a 的失活是否会导致高骨量表型。  通过救援和遗传上位实验测试骨钙素是否对交感神经和/或副交感神经张力解释了其对骨量增长的调节。