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: 8056646
• 负责人: DEBRA J. WOLGEMUTH
• 金额: $ 24.96万
• 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/8056646
• 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甲酸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男性避孕的新方法。全反式维甲酸（ATRA）是维生素A的一种活性代谢物，至少部分通过与类固醇激素超家族的核受体维甲酸受体（RARs）结合来发挥其功能。通过RARa受体的ATRA信号的重要性已经在小鼠的基因靶向中得到证实：RARa缺乏的雄性小鼠不育，精子发生缺陷与维生素a缺乏（VAD）动物相似。在先前用泛rar拮抗剂BMS-189453治疗动物的“睾丸毒性”观察之后，我们现在已经证明，精子发生确实受到抑制，而且这种诱导的不育是可逆的。这表明BMS-189453有潜力作为一种新的、非类固醇激素为基础的男性避孕方法。本研究的重点是在小鼠模型中使用RAR泛拮抗剂BMS-189453来抑制体内精子发生。提出了三个综合目标，其范围从解决有关剂量水平和剂量长度以最大化功效的非常应用的问题到阐明药物作用的细胞和分子靶点。第一个特异性目标将i)延长治疗时间，以确定抑制精子发生的最长时间，之后可以恢复正常的精子发生；Ii)评估比我们初步实验中使用的更低剂量的药物是否能有效抑制精子发生；Iii)确定仍有效的最佳剂量上下范围，以规范给药方案；iv)检查恢复生育后产生的后代是否正常生长。VAD、泛拮抗剂BMS-189453治疗以及特异性缺乏RARa受体都会导致精细胞排列和精子形成缺陷。特异性Aim 2将确定类视黄醛信号的细胞靶标，以及它们如何在缺乏信号的情况下被破坏，从而导致这些特征性异常。最后，Aim 3将验证BMS-189453的至少一些作用是在转录水平上介导的假设，通过识别那些表达被所有三种rar抑制而改变的基因，与仅缺乏RARa的睾丸和正常小鼠的变化相比，使用微阵列分析。