Effects of brain-selective estradiol on gene expression and female sex behavior
脑选择性雌二醇对基因表达和女性性行为的影响
基本信息
- 批准号:8712531
- 负责人:
- 金额:$ 16.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-05 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse effectsAmyotrophic Lateral SclerosisAndrogensAnxietyBindingBlood - brain barrier anatomyBlood CirculationBrainBreastChronicClinicalClinical TreatmentDataDiseaseDoseEffectivenessEnzymesEstradiolEstradiol ReceptorsEstrogen ReceptorsEstrogen TherapyEstrogensFemaleGene ExpressionHealthHealth StatusHormonesHot flushesHypoactive Sexual Desire DisorderImpaired cognitionInternationalLaboratoriesLeadLifeLiverLordosisMacaca mulattaMammalsMammary Gland ParenchymaMammary glandMeasuresMenopauseMental DepressionMental HealthMethodsModelingMonkeysMotivationOperative Surgical ProceduresOvariectomyPeripheralPituitary GlandPostmenopauseProdrugsProgesteroneProgestinsQuality of lifeRattusReportingRiskRodent ModelSerumSex BehaviorSexual PartnersSexualitySleep DisordersSpinal cord injurySymptomsSystemTestingTestosteroneTherapeutic EffectTissuesTreatment EffectivenessUterine CancerUterusWomancancer riskcompare effectivenessdosageeffective therapyemotional distresshormone therapyimprovedin vivointerestmalignant breast neoplasmnovelosmotic minipumpphysical conditioningproliferative phase Menstrual cyclepsychological distresspublic health relevanceresponsesatisfaction
项目摘要
DESCRIPTION (provided by applicant): There is an unmet need for new and safer estrogen therapies (ET) to treat the symptoms associated with low levels or a lack of estrogens, including decreased sexual motivation, hot flushes, sleep disorders, depression/anxiety, brain and spinal cord trauma, amyotrophic lateral sclerosis, and cognitive dysfunction. Currently only estrogens alone or in combination with progestins or androgens are available to treat these conditions, including natural or surgical menopause. However, many women cannot or do not want to take estrogens because of their potential side effects, the most critical of which are the effects of estrogen on the uterus and the breast. However, estrogen insufficiency contributes to post-menopausal decline in sexual desire that can lead to female sexual desire disorder (FSDD). Current hormonal therapies for FSDD use treatment with an estrogen and testosterone, but their effectiveness is limited. Estradiol by itself can reinstate sexual desire if given at dosages that produce midfollicular serum estradiol levels (100-300pg/ml). However, at such dosages there are concerns about the risk of breast or uterine cancer, thus all current FSDD treatments use hypoestrogenic treatment (20pg/ml) in conjunction with testosterone when larger amounts of estradiol would likely increase treatment effectiveness. Here we investigate a novel and potentially safe estrogen therapy using 10b,17b-dihydroxyestra 1,4 dien-3-one (DHED) to reinstate sexual receptivity and sexual motivation in rat and monkey models. DHED is an inactive precursor of estradiol; it does not bind to estradiol receptors and thus produces no estrogenic effects in its native form. However, an enzyme converts DHED to estradiol. Our preliminary evidence suggests that this enzyme is only expressed in the CNS thus potentially making DHED a brain-selective prodrug for 17b-estradiol (E2). DHED, which crosses the blood brain barrier, would be inactive outside of the brain, but would deliver effective amounts of E2 to
the brain. We propose to use sexual behavior as a model estrogen-responsive system with which to test DHED's potential therapeutic effects. Induction of lordosis in ovariectomized females rats using a sequential DHED and progesterone treatment will test the central activity of DHED. We will then use an ovariectomized monkey model of female sexual initiation to test DHED's efficacy in increasing sexual desire. Dr. Prokai will synthesize DHED for this project and undertake in vivo studies on conversion of DHED to E2. Dr. Merchenthaler's lab will investigate estradiol induced gene expression in the brain and periphery after acute or chronic DHED treatment and investigate DHED's capacity to active female rat sexual receptivity. Dr. Wallen's lab will undertake studies of female rhesus monkey sexual initiation during DHED treatment. Preliminary data from rodent models of hypoestrogenic conditions show that DHED is a brain-selective bioprecursor produg for E2, and is likely to be a safe and effective treatment of conditions due to the lack of estrogens (ovariectomy) or low levels of estrogens (menopause). If successful these studies will revolutionize the treatment of clinical problems resulting from hypoestrogenic conditions.
描述(申请人提供):有一个新的和更安全的雌激素疗法(ET)的需求尚未得到满足,以治疗与低水平或缺乏雌激素相关的症状,包括性动机减退、潮热、睡眠障碍、抑郁/焦虑、脑和脊髓创伤、肌萎缩侧索硬化症和认知功能障碍。目前,只有雌激素单独或与孕激素或雄激素联合用于治疗这些疾病,包括自然或外科更年期。然而,许多女性不能或不想服用雌激素,因为它们有潜在的副作用,其中最关键的是雌激素对子宫和乳房的影响。然而,雌激素不足会导致绝经后性欲下降,从而导致女性性欲障碍(FSDD)。目前治疗FSDD的激素疗法使用雌激素和睾酮,但其有效性有限。如果给药剂量达到卵泡中期血清雌二醇水平(100-300pg/ml),雌二醇本身就可以恢复性欲。然而,在这样的剂量下,人们担心患乳腺癌或子宫癌的风险,因此目前所有的FSDD治疗都使用低雌激素治疗(20pg/ml)和睾酮,而更大剂量的雌二醇可能会增加治疗效果。在这里,我们研究了一种新的潜在安全的雌激素疗法,使用10b,17b-二羟基-1,4-二烯-3-酮(DHED)来恢复大鼠和猴子模型的性接受和性动机。DHED是雌二醇的非活性前体;它不与雌二醇受体结合,因此不会产生天然形式的雌激素效应。然而,一种酶可以将DHED转化为雌二醇。我们的初步证据表明,这种酶只在中枢神经系统中表达,因此可能使DHed成为17b-雌二醇(E2)的大脑选择性前体药物。穿过血脑屏障的DHED在脑外不活跃,但会将有效数量的E2输送到
大脑。我们建议使用性行为作为雌激素反应系统的模型,用来测试DHED的潜在治疗效果。使用DHED和黄体酮的顺序治疗诱导去卵巢雌性大鼠的前凸,将测试DHED的中枢活性。然后,我们将使用切除卵巢的雌性性行为启动的猴子模型来测试DHED在提高性欲方面的效果。Prokai博士将为这个项目合成DHed,并进行将DHed转化为E2的体内研究。Merchenthaler博士的实验室将研究在急性或慢性DHed治疗后雌激素诱导的大脑和外周基因表达,并研究DHed激活雌性大鼠性接受能力的能力。沃伦博士的实验室将对雌性恒河猴在脱氢表雄酮治疗期间的性行为启动进行研究。来自雌激素水平低下的啮齿动物模型的初步数据显示,DHED是一种脑部选择性生物递归药物,可产生E2,很可能是一种安全有效的治疗缺乏雌激素(卵巢切除)或低水平雌激素(更年期)的疾病。如果成功,这些研究将彻底改变雌激素水平低下引起的临床问题的治疗方法。
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)
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ISTVAN Jozsef MERCHENTHALER其他文献
ISTVAN Jozsef MERCHENTHALER的其他文献
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{{ truncateString('ISTVAN Jozsef MERCHENTHALER', 18)}}的其他基金
Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model
在先进的转化动物模型中脑选择性雌激素疗法治疗更年期潮热
- 批准号:
10534761 - 财政年份:2021
- 资助金额:
$ 16.38万 - 项目类别:
Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model
在先进的转化动物模型中脑选择性雌激素疗法治疗更年期潮热
- 批准号:
10327690 - 财政年份:2021
- 资助金额:
$ 16.38万 - 项目类别:
Effect of PACAP on the progression of Parkinson's disease in chronic mouse model
PACAP对慢性小鼠帕金森病进展的影响
- 批准号:
9317792 - 财政年份:2017
- 资助金额:
$ 16.38万 - 项目类别:
Establishment of a primate model for menopausal hot flushes
灵长类动物更年期潮热模型的建立
- 批准号:
9262118 - 财政年份:2016
- 资助金额:
$ 16.38万 - 项目类别:
Effects of brain-selective estradiol on gene expression and female sex behavior
脑选择性雌二醇对基因表达和女性性行为的影响
- 批准号:
8598625 - 财政年份:2013
- 资助金额:
$ 16.38万 - 项目类别:
Hot Flushes and SNPs of the Norepinephrine and Serotonin Transporter Genes
潮热以及去甲肾上腺素和血清素转运蛋白基因的 SNP
- 批准号:
7990619 - 财政年份:2011
- 资助金额:
$ 16.38万 - 项目类别:
Hot Flushes and SNPs of the Norepinephrine and Serotonin Transporter Genes
潮热以及去甲肾上腺素和血清素转运蛋白基因的 SNP
- 批准号:
8245713 - 财政年份:2011
- 资助金额:
$ 16.38万 - 项目类别:
Novel Treatment of menopausal hot flushes with an extradiol prodrug
用额外二醇前药治疗更年期潮热的新方法
- 批准号:
7657235 - 财政年份:2009
- 资助金额:
$ 16.38万 - 项目类别:
Novel treatment of menopausal hot flushes with an estradiol prodrug
用雌二醇前药治疗更年期潮热的新方法
- 批准号:
7769500 - 财政年份:2009
- 资助金额:
$ 16.38万 - 项目类别:
Novel Treatment of Menopausal Hot Flushes with an Extradiol Prodrug
用 Extradiol 前药治疗更年期潮热的新方法
- 批准号:
7811694 - 财政年份:2009
- 资助金额:
$ 16.38万 - 项目类别:
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