Neuronal control of bone mass by Sirt1

Sirt1 对骨量的神经元控制

基本信息

批准号：
8934490
负责人：
STAVROULA KOUSTENI
金额：
$ 53.81万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934490
关键词：
Accounting Address Adenoviruses Adrenergic beta-Antagonists Adult Affect Age-Related Bone Loss Aging Animals Bone Resorption Bone remodeling Brain Brain Stem Brown Fat Catecholamines Cells Communication Cues Data Endocrine Enzymes Epinephrine Event Genetic Goals Histone Deacetylase Homeostasis Hormones Human Knowledge Light Link Longevity Mammals Mediating Mediator of activation protein Metabolic Modeling Molecular Monoamine Oxidase A Mus Neurons Neurotransmitters Nicotinamide adenine dinucleotide Norepinephrine Organ Osteoblasts Osteoclasts Osteocytes Osteogenesis Output Pathway interactions Phenotype Physiological Physiology Progress Reports Proteins Regulation Selective Serotonin Reuptake Inhibitor Serotonin Signal Pathway Signal Transduction Sirtuins Site Skeleton Sympathetic Nervous System Tissues Transgenic Mice Up-Regulation Urine base bone bone loss bone mass bone strength cofactor extracellular improved locus ceruleus structure mind control overexpression research study skeletal

项目摘要

Project Summary – Project #2 Similar to most organs, the various functions of the skeleton are influenced by extracellular cues, hormones and neurotransmitters. One type of neuronal regulation of bone mass is the one initiated by the neurotransmitter serotonin that favors bone mass accrual by inhibiting the activity of the sympathetic nervous system. This observation raises questions about the transcriptional mechanisms regulating brain serotonin accumulation and catecholamine synthesis. In addressing this question we have found that the histone deacetylase Sirt1 is a transcriptional modulator of the neuronal control of bone mass. A generalized but modest increase in Sirt1 expression (TgSirt1) in transgenic mice compromises bone mass by suppressing bone formation and by promoting bone resorption. The opposite effects of Sirt1 on the two compartments of bone remodeling correlate with an increase in the activity of the sympathetic nervous system (SNS). Three additional observations implicated the SNS as a mediator of the skeletal actions of Sirt1. First, Ucp1 expression in brown fat and catecholamine levels are increased in TgSirt1 mice. Second, pharmacological inhibition of the SNS activity in TgSirt1 mice fully restores osteoblast and osteoclast numbers and rescues the low bone mass phenotype of these animals. Third, and more directly, adenovirus-mediated deletion of Sirt1 in the brain decreases SNS activity and increases bone mass by increasing bone formation and suppressing bone resorption. Hence, our data suggest that neuronal Sirt1 controls bone mass by increasing SNS signaling. Sirt1 may do so by increasing expression of monoamine oxidase A (MAO-A), a Sirt1 target that reduces serotonin levels in the brain and/or by suppressing serotonin synthesis in the brainstem or by modulating sympathetic tone in the locus coeruleus. This application intends to identify Sirt1 site(s) of action in the brain, osteoblasts. osteocytes and osteoclasts in the aging skeleton, to demonstrate genetically that the SNS mediates the skeletal effects of Sirt1, to determine whether brainstem, locus coeruleus or MAO-A-expressing neurons is the specific brain site(s) through which Sirt1 regulates skeletal homeostasis and to evaluate the respective contribution of MAO-A and Tph2 in the Sirt1- dependent regulation of bone mass.

项目摘要 – 项目 #2 与大多数器官类似，骨骼的各种功能都受到细胞外物质的影响。提示、激素和神经递质是骨量的一种神经元调节。一种由神经递质血清素引发的过程，通过抑制这一观察结果提出了关于交感神经系统活动的问题。调节大脑血清素积累和儿茶酚胺的转录机制在解决这个问题时，我们发现组蛋白脱乙酰酶 Sirt1 是一种骨量神经控制的转录调节剂。普遍但适度。转基因小鼠中 Sirt1 表达（TgSirt1）的增加会通过以下方式损害骨量： Sirt1 抑制骨形成并促进骨吸收的相反作用。骨重塑的两个区室与骨活性的增加相关另外三个观察结果表明 SNS 是一种神经系统。 Sirt1 骨骼作用的介体首先，Ucp1 在棕色脂肪和中的表达。 TgSirt1 小鼠中儿茶酚胺水平增加其次，药理学抑制。 TgSirt1 小鼠的 SNS 活性完全恢复了成骨细胞和破骨细胞的数量，并挽救了这些动物的低骨量表型第三，也是更直接的，腺病毒介导的。大脑中 Sirt1 的缺失会降低 SNS 活性，并通过增加骨量来增加骨量。因此，我们的数据表明神经元。 Sirt1 通过增加 SNS 信号来控制骨量。单胺氧化酶 A (MAO-A) 的表达，这是 Sirt1 的一个靶标，可降低血清素水平大脑和/或通过抑制脑干中的血清素合成或通过调节交感神经蓝斑中的音调该应用旨在识别大脑中的 Sirt1 作用位点，老化骨骼中的成骨细胞和破骨细胞，从遗传学上证明 SNS介导Sirt1的骨骼效应，以确定是否脑干、蓝斑或 MAO-A 表达神经元是 Sirt1 调节骨骼的特定大脑位点稳态并评估 MAO-A 和 Tph2 在 Sirt1- 中各自的贡献骨量的依赖性调节。