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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：
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.

项目总结/文摘