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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：
9764336
负责人：
Gerard Karsenty
金额：
$ 38.05万
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/9764336
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.

项目摘要多年来，神经元控制骨量的存在已经得到了各种各样的证实。 kind.虽然这些绝不是神经元控制骨量的唯一例子，但交感神经元控制骨量的例子并不少见。神经系统通过阻碍骨形成来抑制骨量增加，而副交感神经系统通过抑制骨形成来抑制骨量增加。系统有利于骨量增加。然而，神经元对骨量增加的调节从未被研究过探索作为一种可能的手段，探索骨量表型所造成的各种成骨细胞的缺乏，衍生蛋白质。同样，神经元控制骨量的重要性往往没有得到重视。在颅面区域进行了研究。这是令人惊讶的，因为头骨和面部骨骼中的许多成骨细胞起源于神经嵴细胞骨钙素是骨中最丰富的非胶原蛋白细胞外基质，其缺乏导致知之甚少的高骨量表型。骨钙也是一种激素，在其与本文所述新型受体结合后，应用，脑中儿茶酚胺的合成，从而交感神经的活性系统中心。独立于该函数，如本申请另一组初步结果所示，骨钙素通过它的第一个受体Cyprc 6a发出信号，抑制副交感神经的活性，神经系统骨钙素对自主神经系统的两种调节方式都可能阻碍骨大量应计。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。解释到现在：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在颅面区域以及其他区域对骨量的调节，的骨架。本申请的具体目的是：为了确定前脑中Gpr 158的失活是否会导致高骨量，降低交感神经张力。为了确定Gprc 6a在节后副交感神经元中的失活是否会导致高骨量表型。通过拯救和遗传上位性实验来检测骨钙素对骨形成的调节是否与骨形成有关。交感神经和/或副交感神经张力解释了其对骨量增加的调节。