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: 9055741
• 负责人: DEBRA J. WOLGEMUTH
• 金额: $ 27.24万
• 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/9055741
• 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 Contraceptive Agents; Male Sterility; Modeling; Molecular; Monkeys; Mus; Nuclear; Nuclear Receptors; Oral Administration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Primates; Process; Protein Isoforms; Rattus; 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; pre-clinical trial; receptor; research study; restoration; retinoic acid receptor alpha; sertoli cell; spermatogenic epithelium structure; steroid hormone; transcription factor; transcriptome sequencing; treatment response; 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（由申请人提供）：饮食中的视黄醇（维生素A）和类维生素A信号对睾丸正常发育和分化的重要性已被认识多年。信号传导部分通过视黄酸受体（RAR）来实现，其中有三种亚型：α、β和γ。我们和其他人已经通过基因靶向显示了通过RARα受体的信号传导的重要性，特别是在精子发生过程中：RARα（Rara-/-）缺陷的小鼠是可行的，但雄性是不育的，表现出类似于VAD饮食的生精上皮缺陷。我们还表明，用口服生物可利用的pan-RAR拮抗剂治疗的小鼠变得不育，具有类似的睾丸异常。我们进一步表明，这种诱导的不育是可逆的，即使每天治疗， 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，正常后代在恢复生育力后由父亲交配。这表明RAR拮抗剂具有作为用于男性避孕的新型非甾体化合物的潜力。我们建议按照以下具体目标发挥这一潜力。具体目标1。鉴于成功使用pan-RAR拮抗剂化合物9诱导雄性不育，并认识到RARα对调节精子发生至关重要，我们建议测试RARα选择性拮抗剂，这些拮抗剂可立即获得，并正在由我们的药物化学家合作者开发，以抑制精子发生。具体目标2。RARα作为转录因子，激活或抑制下游靶基因，拮抗剂的功能是阻断这种转录调控。因此，我们提出，这些下游靶基因本身可能代表干扰精子发生和诱导不育的靶点，特别是如果它们是睾丸特异性的或以睾丸特异性方式起作用。由于精子形成似乎是一个对类维生素A信号调节非常敏感的细胞过程，因此，我们将重点阐明精子细胞相对于基底室的不适当锚定，未能从基底室移位到管腔，以及未能脱离精子形成等的机制。这些实验将涉及检查已知在这些过程中重要的候选基因的表达，以及通过最先进的RNA-Seq分析鉴定新基因。具体目标3。为了追求RAR拮抗剂最终作为男性避孕药，我们建议在非人灵长类动物模型（普通绒猴）中进行小规模试验。目的是通过检查拮抗剂在诱导肿瘤细胞凋亡方面的功效，为未来的临床前试验奠定基础。 不育和恢复生育力。这些研究将与位于圣安东尼奥的西南国家灵长类动物研究中心的科学家合作完成。我们的预测是，泛拮抗剂化合物9将在不诱导不期望的副作用的剂量下以可逆的方式抑制精子发生。