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: 8427386
• 负责人: DEBRA J. WOLGEMUTH
• 金额: $ 23.29万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427386
• 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维生素A信号在精子发生调节中的作用，并利用其基本功能的抑制作为一种新的和新颖的方法来男性避孕。全反式视黄酸（ATRA）是维生素A的活性代谢物，并且至少部分地通过与类固醇激素超家族的核受体（视黄酸受体（RAR））结合来发挥其功能。通过小鼠中的基因靶向已经证明了ATRA信号通过RAR α受体的重要性：RAR α缺陷的雄性小鼠不育，精子发生缺陷与维生素A缺陷（VAD）动物中观察到的缺陷相似。根据先前在用泛RAR拮抗剂BMS-189453处理的动物中观察到的“睾丸毒性”，我们现在已经表明，精子发生确实受到抑制，并且进一步表明，这种诱导的不育是可逆的。这表明BMS-189453有潜力作为一种新型的、基于非类固醇激素的男性避孕方法。本提案特别关注RAR泛拮抗剂BMS-189453在小鼠模型中体内抑制精子发生的用途。提出了三个综合目标，其范围从解决关于剂量水平和长度的非常应用的问题以最大化功效到阐明药物作用的细胞和分子靶点。第一个具体目标是：i）延长治疗持续时间，以确定精子发生抑制的最长时间，之后可以恢复正常的精子发生; ii）评估甚至比我们初步实验中使用的更低剂量的药物是否可以有效抑制精子发生; iii）确定仍然有效的最佳剂量以上和以下的范围，以使给药方案标准化;和iv）检查育性恢复后产生的子代的正常生长。VAD、泛拮抗剂BMS-189453治疗以及缺乏RARa受体都特别导致精子细胞排列和精子形成缺陷。 特定目标2将确定类维生素A信号传导的细胞靶点，以及在缺乏类维生素A信号传导的情况下它们如何被破坏以导致这些特征异常。最后，目标3将使用微阵列分析，与仅缺乏RAR α的睾丸和正常小鼠中观察到的变化相比，通过鉴定其表达因抑制所有三种RAR α而改变的基因，来检验BMS-189453的至少一些作用在转录水平介导的假设。 公众相关性：拟议的研究将提供关键信息的潜在用途的维甲酸拮抗剂作为一种新的和新颖的方法，男性避孕。这些实验将提供给药方案的数据，以最大限度地提高疗效，同时最大限度地减少化合物暴露，同时确保可逆性。男性避孕的非激素策略将为希望采取其他计划生育方法的夫妇和世界各地人口过多的国家提供健康益处。