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: 8726695
• 负责人: DEBRA J. WOLGEMUTH
• 金额: $ 27.52万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726695
• 关键词: Adverse effects; Aftercare; All-Trans-Retinol; Animals; Binding; Bioavailable; Callithrix jacchus jacchus; Candidate Disease Gene; Cell physiology; Chemicals; Collaborations; Contraceptive Agents; Defect; Development; Diet; Dose; Drug usage; Excision; Exhibits; Failure; Fathers; Female; Fertility; Future; Gene Expression; Gene Targeting; Genes; Goals; Health; Hormonal; Hormones; Infertility; Lead; Male Contraceptions; Male Contraceptive Agents; Male Sterility; Modeling; Molecular; Monkeys; Mus; Nuclear; Nuclear Receptors; Oral Administration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Primates; Process; Protein Isoforms; Rattus; Relative (related person); Reporting; Research; Retinoic Acid Receptor; Retinoid Receptor; Retinoids; Scientist; Signal Transduction; Specificity; Spermatids; Spermatogenesis; Staging; Sterility; Testing; Testis; Toxic effect; Toxicology; Transcriptional Regulation; Tretinoin; Tubular formation; Vitamin A; Withholding Treatment; Work; activating transcription factor; base; genetic manipulation; loss of function; male; men; mouse model; nonhuman primate; novel; preclinical study; receptor; research study; response; restoration; retinoic acid receptor alpha; sertoli cell; spermatogenic epithelium structure; steroid hormone; transcription factor; transcriptome sequencing; working group

DESCRIPTION (provided by applicant): The importance of dietary retinol (vitamin A) and retinoid signaling for normal development and differentiation in the testis has been recognized for many years. Signaling is effected in part through the retinoic acid receptors (RARs), of which there are three isoforms, α, ß, and γ. We and others have shown the importance of signaling via the RARα receptor in particular during spermatogenesis by gene targeting: mice deficient in RARα (Rara-/-) are viable but the males are sterile, exhibiting defects in the seminiferous epithelium resembling those seen VAD diet. We have also shown that mice treated with an orally bioavailable pan-RAR antagonist become sterile, with similar testicular abnormalities. We have further shown that this induced sterility is reversible even with daily treatments for as long as 4 months upon cessation of drug treatment. Importantly, no detectable side effects were observed at these low doses and normal progeny were sired by fathers after restoration of fertility. This suggested that RAR-antagonists have potential as novel, non-steroidal compounds for male contraception. We propose to pursue this potential as outlined in the following specific aims. Specific Aim 1. Given the successful use of the pan-RAR antagonist compound 9 to induce male sterility and the recognition that it is RARα that is critical for regulating spermatogenesis, we propose to test RARα-selective antagonists that are immediately available and are being developed by our medicinal chemist collaborators in inhibiting spermatogenesis. Specific Aim 2. RARα functions as a transcription factor, activating or repressing downstream target genes and antagonists function to block this transcriptional regulation. We therefore propose that such downstream target genes may themselves represent targets for interfering with spermatogenesis and inducing sterility, particularly if they are either testis-specific or function in a testisspecific manner. As spermiation appears to be a cellular process that is exquisitely sensitive to modulation of retinoid signaling, we will therefore focus on elucidating the mechanisms responsible for the improper anchorage of spermatids relative to the basal compartment, failure to translocate from basal compartment to the tubular lumen, and failure to disengage for spermiation, etc. at the cellular and molecular levels. These experiments will involve examining the expression of candidate genes known to be important in these processes and the identification of new genes by state-of-the-art RNA-Seq analysis. Specific Aim 3. To pursue RAR-antagonists ultimately as contraceptives in men, we propose to undertake a small scale trial in a non-human primate model (the common marmoset). The goal is to set the stage for future pre-clinical trials by examining the efficacy of antagonists with regard to induction of sterility and restoration of fertility. These studies will be done in collaboration with scientistsat the Southwest National Primate Research Center in San Antonio. Our prediction is that the pan-antagonist compound 9 will inhibit spermatogenesis in a reversible manner at doses that will not induce undesirable side effects.

描述（由适用提供）：多年来已经确认了饮食中视黄醇（维生素A）和视黄素信号对睾丸正常发育和分化的重要性。信号通过视黄酸受体（RARS）部分影响，其中三种同工型α，ß和γ。我们和其他人表明，通过基因靶向精子发生，特别是通过RARα受体进行信号传导的重要性：缺乏RARα（RARA-/ - ）的小鼠可行，但男性是无菌的，在半肥中表皮上的缺陷，类似于那些见过VAD饮食的半含量上皮。我们还表明，用口服可生物可用的泛抗拮抗剂治疗的小鼠变得无菌，具有相似的检测异常。我们进一步表明，即使每日治疗长期处理，这种诱发的无菌性也是可逆的 停止药物治疗后4个月。重要的是，在这些低剂量下未观察到可检测到的副作用，并且在恢复生育能力后，父亲锯齿状。这表明RAR-Antagonists具有新型的非甾体类化合物的潜力，可用于男性违规。我们建议在以下特定目标中概述的那样追求这一潜力。特定的目标1。鉴于泛杆拮抗剂9的成功使用诱导男性特异性目标2。RARα的功能作为转录因子，激活或表达下游靶基因和拮抗剂的功能来阻止该转录调节。因此，我们建议这样的下游靶基因本身可以代表干扰精子发生和诱导的无菌性的靶标，尤其是如果它们是特异性睾丸特异性的，或者以睾丸特异性的方式起作用。因此，由于精子似乎是一个细胞过程，对类维生素性信号的调节完全敏感，因此，我们将着重于阐明相对于基本隔室的精子发生不当锚定的机制，未能从基本隔室转移到管状腔室，并在细胞和分子级别上失去精子级别等。这些实验将涉及研究已知在这些过程中已知重要的候选基因的表达，并通过最新的RNA-Seq分析来鉴定新基因。具体目标3。要最终作为男性避孕剂追求RAR-Antagonists，我们建议在非人类的私人模型（共同的Marmoset）中进行小型试验。目的是通过检查拮抗剂在诱导方面的有效性来为未来的临床前试验奠定基础 无菌和生育能力的恢复。这些研究将与圣安东尼奥的西南国家灵长类动物研究中心合作进行。我们的预测是，泛雄性化合物9将以可逆的方式抑制精子发生，而不会引起不明显的副作用。