Role of estrogen receptor-a in aging and sex-specific responses to 17a-estradiol

雌激素受体-a 在衰老和对 17a-雌二醇的性别特异性反应中的作用

• 批准号: 10662459
• 负责人: Michael B Stout
• 金额: $ 51.52万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662459
• 关键词: 4-vinylcyclohexene diepoxide; Ablation; Acute; Affinity; Age Months; Aging; Binding; Brain; Caloric Restriction; Cells; Chronic; Chronic Disease; Coupled; Dependovirus; Disease; Dose; Eating; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Fatty Liver; Female; Genetic; Goals; Health; Health Benefit; Homeostasis; Human; Hypothalamic structure; Incidence; Infusion procedures; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Liver; Longevity; LoxP-flanked allele; Mediating; Metabolic; Metabolism; Molecular Target; Mus; Neurons; Obesity; Outcome; Ovarian; Ovariectomy; Pathology; Pathway interactions; Play; Production; Rattus; Reporting; Research; Role; Sex Differences; Signal Transduction; Sirolimus; Site; Testing; aged; blood glucose regulation; burden of illness; designer receptors exclusively activated by designer drugs; druggable target; frailty; genetic approach; glucose tolerance; healthspan; improved; in vivo evaluation; indexing; inflammatory marker; insight; insulin sensitivity; male; middle age; novel; pharmacologic; programs; receptor; response; sex; sexual dimorphism

PROJECT SUMMARY/ABSTRACT Several pharmacological compounds have shown promise as interventional strategies for extending longevity. One recently studied compound shown to improve healthspan and longevity is 17α-estradiol (17α-E2). 17α-E2 is a diastereomer of 17β-estradiol (17β-E2) with considerably less binding affinity for classical estrogen receptors than 17β-E2. The NIA Interventions Testing Program has shown that 17α-E2 extends lifespan in male, but not female, mice at two doses. The mechanisms that promote sexually divergent responses to 17α-E2 are poorly understood and are aligned with the increasing recognition that aging and the incidence of specific diseases often differ between the sexes. This project will explore potential mechanisms by which 17α-E2 modulates aging and metabolism in a sex-specific manner. Successful completion of this project will determine: 1) if estrogen receptor α (ERα) is required for 17α-E2 to elicit benefits on healthspan, disease pathology, and lifespan, 2) if 17α-E2 modulates metabolic parameters predominantly through hypothalamic ERα-mediated signaling, 3) if the beneficial effects of 17α-E2 on metabolic parameters can be mimicked by activating hypothalamic ERα through chemogenetic approaches, and 4) if the elimination of endogenous estrogen production render female mice responsive to 17α-E2-mediated effects on metabolism, and if this is ERα dependent. We hypothesize that 17α- E2 signals through ERα in male mice to enhance healthspan and longevity and that these effects are at least partially mediated through the hypothalamus. We also hypothesize that female mice lacking endogenous estrogens will beneficially respond to 17α-E2 in an ERα-dependent manner. Aim 1: Determine if 17α-E2 improves healthspan and lifespan in an ERα-dependent manner. We will evaluate the effects of chronic 17α-E2 treatment on indices of healthspan and lifespan in wild-type and global ERαKO mice. Aim 2: Determine if 17α- E2 elicits metabolic benefits through ERα in the hypothalamus. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in mice with a hypothalamus-specific deletion of ERα using stereotaxic delivery of adeno-associated virus (AAV) that drives expression of Cre in ERα-flox mice. Aim 3: Determine if chemogenetic activation of hypothalamic ERα-expressing cells can mimic the health benefits observed with 17α- E2 treatment. We will evaluate the effects of stimulating hypothalamic ERα-expressing cells on metabolic and healthspan outcomes via site-specific expression of AAV Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in ERα-flox mice. Aim 4: Determine if the elimination of endogenous estrogen production renders female mice responsive to 17α-E2 treatment. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in wild-type and global ERαKO female mice undergoing ovariectomy or 4-vinylcyclohexene diepoxide-induced ovarian insufficiency. The ultimate goal of this research is to develop sex-specific pharmacological interventions for attenuating aging and chronic diseases.

项目概要/摘要 几种药理学化合物已显示出作为延长寿命的干预策略的前景。 最近研究的一种化合物被证明可以改善健康寿命和寿命，那就是 17α-雌二醇 (17α-E2)。 是 17β-雌二醇 (17β-E2) 的非对映异构体，与经典雌激素受体的结合亲和力显着降低 NIA 干预测试计划表明 17α-E2 可以延长男性的寿命，但不能延长男性的寿命。 两种剂量的雌性小鼠，促进对 17α-E2 的性别差异反应的机制很差。 人们越来越认识到衰老和特定疾病的发病率 该项目将探索 17α-E2 调节衰老的潜在机制。 该项目的成功完成将决定： 1) 是否有雌激素。 17α-E2 需要受体 α (ERα) 才能对健康寿命、疾病病理学和寿命产生益处，2) 如果 17α-E2 主要通过下丘脑 ERα 介导的信号传导调节代谢参数，3) 如果 17α-E2 对代谢参数的有益作用可以通过激活下丘脑 ERα 来模拟 化学遗传学方法，以及 4) 消除内源性雌激素的产生是否会导致雌性小鼠 对 17α-E2 介导的代谢作用做出反应，如果这是 ERα 依赖性的，我们会努力解决这一问题。 E2 通过雄性小鼠的 ERα 发出信号，以延长健康寿命和寿命，并且这些作用至少是 我们还研究了缺乏内源性的雌性小鼠。 雌激素将以 ERα 依赖性方式对 17α-E2 产生有益反应 目标 1：确定 17α-E2 是否存在。 以 ERα 依赖性方式改善健康和寿命 我们将评估慢性 17α-E2 的影响。 对野生型和整体 ERαKO 小鼠的健康寿命和寿命指数的治疗目标 2：确定 17α- 是否有效。 E2 通过下丘脑中的 ERα 引发代谢益处我们将评估 17α-E2 治疗的效果。 使用立体定位技术对下丘脑特异性删除 ERα 的小鼠的代谢和健康寿命参数进行研究 递送驱动 ERα-flox 小鼠 Cre 表达的腺相关病毒 (AAV) 目标 3：确定是否。 下丘脑 ERα 表达细胞的化学遗传学激活可以模拟 17α- 观察到的健康益处 我们将评估刺激下丘脑 ERα 表达细胞对代谢和 E2 治疗的影响。 通过 AAV Gq 耦合设计受体的位点特异性表达独家激活的健康寿命结果 目标 4：确定内源性雌激素是否被消除。 生产使雌性小鼠对 17α-E2 治疗产生反应 我们将评估 17α-E2 治疗的效果。 对接受卵巢切除术的野生型和整体 ERαKO 雌性小鼠的代谢和健康寿命参数的影响 或4-乙烯基环己烯双环氧化物诱发的卵巢功能不全这项研究的最终目标是开发。 用于减轻衰老和慢性疾病的针对性别的药物干预措施。

项目成果

Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice.

• DOI: 10.1016/j.exger.2021.111669
• 发表时间: 2022-03
• 期刊: Experimental gerontology
• 影响因子: 3.9
• 作者: Isola JVV;Zanini BM;Hense JD;Alvarado-Rincón JA;Garcia DN;Pereira GC;Vieira AD;Oliveira TL;Collares T;Gasperin BG;Stout MB;Schneider A
• 通讯作者: Schneider A

17α-Estradiol Mitigates the Negative Effects of High-Fat Feeding in Both Male and Female Mice.

17α-雌二醇可减轻雄性和雌性小鼠高脂肪喂养的负面影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Bubak,MatthewP;Mann,ShivaniN;Broomfield,MatleE;Stout,MichaelB;Miller,BenjaminF
• 通讯作者: Miller,BenjaminF

Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis.

• DOI: 10.1002/jor.25322
• 发表时间: 2022-12
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Liu, Huanhuan;Witzigreuter, Luke;Sathiaseelan, Roshini;Agbaga, Martin-Paul;Brush, Richard S.;Stout, Michael B.;Zhu, Shouan
• 通讯作者: Zhu, Shouan

Dasatinib and quercetin increase testosterone and sperm concentration in mice.

达沙替尼和槲皮素可增加小鼠的睾酮和精子浓度。

• DOI: 10.1556/2060.2023.00192
• 发表时间: 2023
• 期刊: Physiology international
• 影响因子: 1.4
• 作者: Garcia,DrieleN;Hense,JéssicaD;Zanini,BiankaM;Isola,JoséVV;Pradiee,Jorgea;Prosczek,JulianeB;Alvarado-Rincón,JoaoA;Mondadori,RafaelG;Mason,JeffreyB;Brieño-Enríquez,MiguelA;Barros,CarlosC;Stout,MichaelB;Masternak,MichalM
• 通讯作者: Masternak,MichalM