Arcuate ERa Signaling in Central Control of Female Bone Metabolism

女性骨代谢中枢控制的弓形 ERa 信号传导

基本信息

批准号：
10634591
负责人：
HOLLY A. INGRAHAM
金额：
$ 46.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10634591
关键词：
Ablation Address Affect Age-Related Bone Loss Biological Assay Bone Density Brain Cell Nucleus Central Nervous System Data Dose Endocrine Energy Metabolism Estradiol Estrogen Receptor alpha Estrogens Exhibits Exposure to Female Gatekeeping Genetic Genetic Models Goals Gonadal Steroid Hormones Health Hormonal Human Hypothalamic structure In Vitro KISS1 gene Knowledge Leptin Longevity Medial Mediating Metabolic Metabolism Modeling Molecular Mus Nervous System control Neurons Osteogenesis Osteoporosis Parabiosis Peripheral Pharmaceutical Preparations Pharmacology Phenotype Physiology Public Health Regulation Reporting Reproduction Research Rosaniline Dyes Sex Differences Signal Transduction Structure of nucleus infundibularis hypothalami Testing Testosterone Therapeutic Tissues Virus Work bone bone fracture repair bone mass bone metabolism bone strength cortical bone designer receptors exclusively activated by designer drugs energy balance genetic manipulation hormonal signals in vivo male model building mouse model mutant mutant mouse model neural circuit novel novel therapeutics pharmacologic pre-clinical rational design reproductive fitness response restraint sex skeletal substantia spongiosa translational potential

项目摘要

Project Summary/Abstract In this revised R01 application we will ask how estrogen signaling in the central nervous system controls bone metabolism in a sex dependent manner. It is well known that peripheral estrogen affects bone in both mice and humans. As part of our efforts to understand how estrogen neural circuits in mice affect female metabolism, we discovered that estrogen signaling in the arcuate nucleus (ARC) of the hypothalamus normally suppresses cortical and trabecular bone mass in female mice. Ablating estrogen receptor alpha (ERa) in three intersectional and independent mouse models leads to a striking high bone mass phenotype in female mice; male bones are unaffected. Mutant females exhibit exceptionally dense trabecular and cortical bones, whose strengths surpass other reported mouse models. Stereotaxic- guided deletion of brain ERa confirmed the central origin of this bone phenotype and uncoupled this phenotype from changes in circulating estradiol, testosterone, or leptin. Our work defines central regulation of bone metabolism, alongside reproduction and energy balance, as a fundamental sex- difference in physiology. These data also offer proof for the concept that the brain is a major determinant of female bone metabolism, thus expanding the gatekeeper function of the hypothalamus in energy expenditure to non-classical metabolic tissues, such as bone. Although our research is in the earliest pre-clinical stages, understanding how our models build massively dense and strong bones could transform current rational design of therapeutics for hormonal and age-related bone loss. Why and how female ARC neurons normally inhibit bone metabolism remain a mystery. In the following three aims, we seek to unravel this puzzle. We will define and then confirm which ARC neurons mediate this brain-bone connection, ask if manipulating these neurons via chemogenetics and pharmacology mimics high bone phenotype or normalizes the bone phenotype in mutants, and then begin determining the molecular basis for this sex-dependent high bone phenotype.

项目概要/摘要在这个修订后的 R01 应用程序中，我们将询问中枢神经系统中的雌激素信号如何控制骨代谢以性别依赖性方式进行。众所周知，外周雌激素影响骨骼老鼠和人类。作为我们努力了解雌激素神经回路如何影响小鼠的一部分女性新陈代谢，我们发现雌激素信号传导在女性的弓状核（ARC）下丘脑通常会抑制雌性小鼠的皮质骨和小梁骨量。消除雌激素三个交叉且独立的小鼠模型中的受体α（ERa）导致惊人的高骨雌性小鼠的质量表型；男性骨骼不受影响。突变雌性表现出异常密集小梁骨和皮质骨，其强度超过其他报道的小鼠模型。立体定向- 脑ERa的引导删除证实了这种骨表型的中心起源，并将其解开循环雌二醇、睾酮或瘦素变化的表型。我们的工作定义了中心骨代谢的调节，以及生殖和能量平衡，作为基本的性别生理上的差异。这些数据还证明了大脑是主要决定因素的概念女性骨代谢，从而扩大下丘脑的能量守门人功能非经典代谢组织（例如骨骼）的支出。虽然我们的研究最早在临床前阶段，了解我们的模型如何构建高度致密且坚固的骨骼可以改变当前针对激素和年龄相关骨质流失的合理治疗设计。为什么以及如何女性 ARC 神经元通常会抑制骨代谢仍然是一个谜。为了实现以下三个目标，我们试图解开这个谜题。我们将定义并确认哪些 ARC 神经元介导该脑骨连接，询问通过化学遗传学和药理学操纵这些神经元是否模仿高骨表型或标准化突变体的骨表型，然后开始确定分子这种性别依赖性高骨表型的基础。