Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
基本信息
- 批准号:8413601
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAdverse effectsAffectAgingAgreementAnabolismAndrogensAntioxidantsApoptosisAttenuatedCell SurvivalCellsChemosensitizationCommitDNA BindingDefense MechanismsDendrimersDevelopmentDiseaseEnzymesEquilibriumEstradiolEstrogen ReceptorsEstrogensExcisionFemaleGenerationsGenetic TranscriptionGonadal Steroid HormonesGrowthHomeostasisLongevityMaintenanceMediatingMesenchymalMolecularMuramidaseMusNF-kappa BNuclearOrganOsteoblastsOsteoclastsOsteocytesOsteoporosisOvarianOvariectomyOxidation-ReductionOxidative StressPathway interactionsPhosphorylationProductionReactive Oxygen SpeciesSecondary toSeminal VesiclesSignal TransductionSkeletonThickWeightWorkattenuationbasebonebone cellbone lossbone masscathepsin Kcell typedentin matrix protein 1gain of functionin vivomaleosteoclastogenesisoverexpressionp66(ShcA) proteinpreventprogenitorprotective effectreceptorreproductivesexskeletalsubstantia spongiosatranscription factor
项目摘要
DESCRIPTION (provided by applicant):
Gonadectomy increases the generation of reactive oxygen species (ROS) in the murine skeleton and the adverse effects of the loss of ovarian or testicular function on bone can be prevented by anti-oxidants. Conversely, estrogens or non-aromatizable androgens decrease oxidative stress. The effects of estrogens result from DNA-binding independent actions of the ER1. In full agreement with such a mechanism, an estradiol dendrimer conjugate (EDC) that is not capable of stimulating the nuclear- initiated actions of ER1 reproduces the effects of estradiol on osteoclasts and osteoblasts ; and is as potent as estradiol in preventing oxidative stress and ovariectomy-induced bone loss, without affecting uterine weight. ER1 deletion in cells of the osteoclast lineage (expressing Lys-M) causes loss of cancellous, but not cortical, bone in female mice; while ER1 deletion from mesenchymal progenitors (Prx1 expressing cells) decreases cortical thickness in both females and males. Consistent with the above, ROS attenuate osteoblastogenesis and shorten the lifespan of osteoblasts and osteocytes. On the other hand ROS are required for osteoclast generation, function, and survival. Moreover, loss or gain of function of FoxOs - transcription factors that are an important defense mechanism against oxidative stress (OS) -dramatically alters skeletal homeostasis. Based on these findings it is hypothesized that similar to ER1-mediated effects of estrogens, AR-mediated effects of androgens decrease ROS generation in both osteoblasts and osteoclasts via cell autonomous mechanisms. Conversely, androgen deficiency increases ROS production in either cell type, and in the adult male skeleton this leads to loss of both cancellous and cortical bone. The protective effect of androgens on cancellous bone is mediated primarily via the osteoclast AR and results from decreased osteoclastogenesis and shortened osteoclast lifespan secondary to increased apoptosis. The protective effect of androgens on cortical bone is mediated via both the AR and the ER1 and is caused by attenuation of ROS-induced FoxO activation and the resulting potentiation of Wnt signaling and osteoblastogenesis. The EDC will be protective of cortical bone in gonadectomised males, as it is in females, without affecting male reproductive organs such as seminal vesicles. To advance these interrelated hypotheses, the contribution of cell autonomous effects of androgens on osteoblasts to skeletal homeostasis will be investigated by determining the effects of AR deletion from Prx1, Osx, or DMP1 expressing cells in the skeleton of male mice; and the effects of AR-mediated androgen signaling on ROS and FoxO-activated pathways in vivo and in osteoblastic cells isolated from these mice. Further, the contribution of cell autonomous effects of androgens on osteoclasts to skeletal homeostasis will be studied by determining the effects of AR deletion from LysM and Cathepsin K expressing cells in the skeleton of male mice; and the effects of AR-mediated androgen signaling on ROS-activated pathways in vivo and in osteoclastic cells isolated from these mice. Lastly, the contribution of the ER1 deletion from osteoblastic cells to skeletal homeostasis in the male and the bone sparing efficacy of the EDC in androgen deficient wild type adult male mice will be determined.
描述(由申请人提供):
性腺切除术增加了小鼠骨骼中活性氧(ROS)的产生,抗氧化剂可以预防卵巢或睾丸功能丧失对骨骼的不良影响。相反,雌激素或非芳香化雄激素降低氧化应激。雌激素的作用来自ER 1的DNA结合独立作用。与这种机制完全一致,不能刺激ER 1的核引发作用的雌二醇树枝状聚合物缀合物(EDC)再现雌二醇对破骨细胞和成骨细胞的作用;并且在预防氧化应激和卵巢切除术诱导的骨丢失方面与雌二醇一样有效,而不影响子宫重量。在雌性小鼠中,破骨细胞谱系(表达Lys-M)细胞中的ER 1缺失导致松质骨而不是皮质骨的丢失;而在雌性和雄性小鼠中,间充质祖细胞(表达Prx 1的细胞)中的ER 1缺失降低了皮质厚度。与上述一致,ROS减弱成骨细胞生成并缩短成骨细胞和骨细胞的寿命。另一方面,ROS是破骨细胞生成、功能和存活所必需的。此外,FoxOs -转录因子是对抗氧化应激(OS)的重要防御机制-功能的丧失或获得显著改变了骨骼的稳态。基于这些发现,我们推测,类似于雌激素的ER 1介导的作用,雄激素的AR介导的作用通过细胞自主机制降低了成骨细胞和破骨细胞中ROS的产生。相反,雄激素缺乏会增加任一细胞类型中ROS的产生,并且在成年男性骨骼中,这会导致松质骨和皮质骨的损失。雄激素对松质骨的保护作用主要通过破骨细胞AR介导,并由破骨细胞生成减少和破骨细胞寿命缩短继发于细胞凋亡增加所致。雄激素对皮质骨的保护作用是通过AR和ER 1介导的,并且是由ROS诱导的FoxO激活的减弱以及由此产生的Wnt信号传导和成骨细胞生成的增强引起的。EDC将保护性腺切除雄性的皮质骨,与雌性相同,不会影响雄性生殖器官,如精囊。为了推进这些相互关联的假设,将通过确定雄性小鼠骨骼中Prx 1、Osx或DMP 1表达细胞AR缺失的影响来研究雄激素对成骨细胞的细胞自主作用对骨骼稳态的贡献;以及AR介导的雄激素信号传导对体内和从这些小鼠分离的成骨细胞中的活性氧和FoxO激活途径的影响。此外,雄激素对破骨细胞的细胞自主作用对骨骼稳态的贡献将通过确定雄性小鼠骨骼中表达LysM和组织蛋白酶K的细胞中AR缺失的影响,以及AR介导的雄激素信号传导对体内和从这些小鼠分离的骨细胞中ROS活化途径的影响来研究。最后,将确定成骨细胞中ER 1缺失对雄性动物骨骼稳态的贡献以及EDC在雄激素缺乏野生型成年雄性小鼠中的骨保护功效。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
STAVROS C. MANOLAGAS其他文献
STAVROS C. MANOLAGAS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('STAVROS C. MANOLAGAS', 18)}}的其他基金
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
- 批准号:
8244288 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
- 批准号:
8598056 - 财政年份:2012
- 资助金额:
-- - 项目类别:
MOLECULAR MECHANISMS OF THE SKELETAL EFFECTS OF ESTROGEN IN OLD AGE
雌激素对老年骨骼影响的分子机制
- 批准号:
7094994 - 财政年份:2006
- 资助金额:
-- - 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
- 批准号:
6316954 - 财政年份:2000
- 资助金额:
-- - 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
- 批准号:
6098701 - 财政年份:1999
- 资助金额:
-- - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
-- - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
-- - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
- 批准号:
RGPIN-2018-04753 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discovery Grants Program - Individual