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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：
9916919
负责人：
HOLLY A. INGRAHAM
金额：
$ 46.55万
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/9916919
关键词：
Address Affect Age-Related Bone Loss Biological Assay Bone Density Brain Cell Nucleus Data Dose Endocrine Energy Metabolism Estradiol Estrogen Receptor alpha Estrogens Exhibits Exposure to Female Fracture 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 Neuraxis Neurons Osteogenesis Osteoporosis Parabiosis Peripheral Pharmaceutical Preparations Pharmacology Phenotype Physiology Public Health Regulation Reporting Reproduction Research Rosaniline Dyes Sex Differences Signal Transduction Steroidal Estrogen Structure of nucleus infundibularis hypothalami Testing Testosterone Therapeutic Tissues Translations Virus Work bone bone mass bone metabolism bone strength cortical bone design designer receptors exclusively activated by designer drugs energy balance hormonal signals in vivo intersectionality male mouse model mutant mutant mouse model neural circuit novel novel therapeutics pre-clinical repaired reproductive fitness response sex skeletal substantia spongiosa

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.

项目摘要/摘要在这个修订的R01应用中，我们将询问中枢神经系统中的雌激素信号是如何控制的以性别依赖的方式进行骨骼代谢。众所周知，外周雌激素影响骨质疏松。无论是老鼠还是人类。作为了解小鼠雌激素神经回路如何影响的努力的一部分在女性新陈代谢中，我们发现弓状核(ARC)中的雌激素信号。下丘脑通常会抑制雌性小鼠的皮质和松质骨量。消融雌激素在三种交叉和独立的小鼠模型中，受体α(Era)导致显著的高骨量雌性小鼠的群体表型；雄性骨骼不受影响。突变的雌性动物表现出异常密集的骨小梁和皮质骨，其强度超过其他已报道的小鼠模型。立体定位法- 脑Era的引导缺失证实了这种骨表型的中心起源，并解偶联了这一由于循环中的雌二醇、睾酮或瘦素的变化而产生的表型。我们的工作定义了中心调节骨骼新陈代谢，以及生殖和能量平衡，作为一种基本性- 生理学上的差异。这些数据也为大脑是一个主要决定因素的概念提供了证据改善女性的骨代谢，从而扩大下丘脑的能量把关功能用于非经典新陈代谢组织的支出，如骨骼。虽然我们的研究是最早的临床前阶段，了解我们的模型如何构建大量致密和强壮的骨骼改变目前治疗荷尔蒙和年龄相关性骨丢失的合理设计。为什么以及如何女性ARC神经元通常会抑制骨代谢，这仍然是一个谜。在以下三个目标中，我们试图解开这个谜团。我们将定义并确认哪些ARC神经元调节这一脑骨连接，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或使突变体的骨表型正常化，然后开始确定分子这种性别相关的高骨表型的基础。