Retinoid receptor antagonists as novel male contraceptives

类维生素A受体拮抗剂作为新型男性避孕药

• 批准号: 8537001
• 负责人: DEBRA J. WOLGEMUTH
• 金额: $ 1.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537001
• 关键词: Address; Animals; Binding; Characteristics; Country; Couples; Data; Defect; Dose; Drug effect disorder; Drug usage; Ensure; Family Planning; Fertility; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Health Benefit; Hormonal; Hormones; Length; Male Contraceptions; Male Contraceptive Agents; Mediating; Microarray Analysis; Molecular Target; Mus; Nuclear Receptors; Regimen; Regulation; Retinoic Acid Receptor; Retinoid Receptor; Retinoids; Role; Signal Transduction; Spermatids; Spermatogenesis; Sterility; Testing; Testis; Toxic effect; Tretinoin; Vitamin A; base; cellular targeting; in vivo; male; mouse model; novel; novel strategies; receptor; research study; restoration; steroid hormone; treatment duration

DESCRIPTION (provided by applicant): The overarching goal of these studies is to understand the role of retinoid signaling in the regulation of spermatogenesis and to exploit the inhibition of its essential function as a new and novel approach to male contraception. All trans retinoic acid (ATRA) is an active metabolite of vitamin A and exerts its function at least in part by binding to nuclear receptors of the steroid hormone superfamily, the retinoic acid receptors (RARs). The importance of ATRA signaling via the RARa receptor in particular has been demonstrated by gene targeting in mice: RARa-deficient male mice are sterile with defects in spermatogenesis similar to those seen in vitamin A-deficient (VAD) animals. Following up on previous observations of 'testicular toxicity' in animals treated with the pan-RAR antagonist BMS-189453, we have now shown that indeed, spermatogenesis is inhibited, and further, that this induced sterility is reversible. This suggested that BMS-189453 had potential as a novel, non-steroid hormone-based approach to male contraception. The present proposal focuses specifically on the use of the RAR pan-antagonist BMS-189453 to inhibit spermatogenesis in vivo in the mouse model. Three integrated Aims are proposed, which range in scope from addressing very applied questions with regard to levels and length of dosing to maximize efficacy to elucidating the cellular and molecular targets of the drug's action. The first Specific Aim will i) extend the duration of treatment to determine the maximum period of inhibition of spermatogenesis after which normal spermatogenesis can be restored; ii) assess whether even lower doses of the drug than used in our preliminary experiments can be effective in inhibiting spermatogenesis; iii) determine the range above and below the optimal dose that is still effective in order to standardize the dosing regimen; and iv) examine the progeny that result after the restoration of fertility for their normal growth. VAD, treatment with the pan-antagonist BMS-189453, and lack of the RARa receptor specifically all result in defects in spermatid alignment and spermiation. Specific Aim 2 will determine the cellular targets of retinoid signaling and how are they disrupted in its absence to result in these characteristic abnormalities. Finally, Aim 3 will test the hypothesis that at least some of the effects of BMS-189453 are mediated at the transcriptional level by identifying those genes whose expression is altered by inhibition of all three RARs, as compared to the changes seen in testes lacking only RARa and to normal mice, using microarray analysis. PUBLIC RELEVANCE: The proposed studies will provide critical information on the potential use of retinoid antagonists as a new and novel approach to male contraception. The experiments will provide data on dosing regimens to maximize efficacy while minimizing compound exposure, all the while ensuring reversibility. Non-hormonal strategies for male contraception would provide health benefits to couples desiring alternative family planning approaches and to over-populated countries world-wide.

描述（由申请人提供）：这些研究的总体目标是了解类视黄素信号在调节精子发生中的作用，并利用其必不可少的功能作为一种新的新型男性避孕方法。所有反式视网膜酸（ATRA）都是维生素A的活性代谢产物，并至少部分通过与类固醇激素超家族的核受体（视黄酸受体（RARS）结合）至少通过结合其功能。在小鼠中，基因靶向尤其是通过RARA受体进行ATRA信号传导的重要性：RARA缺陷型雄性小鼠是无菌的，在精子发生中，与维生素A缺乏症（VAD）动物相似的精子发生中的缺陷。跟随以前对用泛抗拮抗剂BMS-189453治疗的动物的“睾丸毒性”的观察结果，我们现在表明，确实抑制了精子发生，进一步抑制了这种诱导的无菌性是可逆的。这表明BMS-189453具有一种新型的，非类固醇激素的方法的潜力。本提案专门针对使用RAR Pan-Antagonist BMS-189453来抑制小鼠模型中体内的精子发生。提出了三个综合目的，范围从范围范围范围从解决有关剂量水平和长度的非常适用的问题，以最大程度地提高功效，以阐明药物作用的细胞和分子靶标。第一个具体目的是i）延长治疗持续时间，以确定可恢复正常精子发生的精子发生的最大抑制周期； ii）评估我们的初步实验中甚至比我们初步实验中使用的剂量更低的药物是否可以有效抑制精子发生； iii）确定在最佳剂量上方和下方的范围，该范围仍然有效，以标准化给药方案； iv）检查生育能力正常生长后的后代。 VAD，用泛抗抗逆转录膜BMS-189453处理，缺乏RARA受体，特别是所有这些都会导致精子比对和精子的缺陷。 特定的目标2将确定类视黄素信号传导的细胞靶标，以及它们在缺席的情况下如何破坏，从而导致这些特征异常。最后，AIM 3将检验以下假设：与仅使用微阵列分析的仅缺乏RARA和正常小鼠的睾丸的变化相比，与仅抑制所有三个RAR的表达改变的基因通过抑制所有三个RAR的表达变化而在转录水平上进行了介导。 公众相关性：拟议的研究将提供有关维生素类拮抗剂作为一种新颖新颖的男性避孕方法的潜在使用的关键信息。这些实验将提供有关给药方案的数据，以最大程度地提高功效，同时最大程度地减少复合暴露，同时确保可逆性。男性避孕的非荷尔蒙战略将为想要替代的计划生育方法和全球人口过剩的夫妇提供健康益处。