Reversal of Spermatogonial Arrest in Mice

逆转小鼠精原细胞停滞

• 批准号: 7372860
• 负责人: Marvin L. Meistrich
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372860
• 关键词: Adolescent; Affect; Androgens; Biological; Body Temperature; Cell Differentiation process; Cells; Defect; Development; Elevation; Event; Experimental Animal Model; Genes; Genetic; Germ Cells; High temperature of physical object; Hormones; Human; In Vitro; Infertility; Lead; Link; Male Infertility; Metabolic; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Oligospermia; Process; Publications; Publishing; RNA Processing; Regulation; Research; Ribosomal RNA; Sperm Count Procedure; Spermatocytes; Spermatogenesis; Spermatogonia; Staging; Temperature; Testing; Testosterone; Toxicant exposure; in vivo; insight; men; sperm cell; spermatogonial arrest; toxicant

DESCRIPTION (provided by applicant): Genetic defects or toxicant exposure often result in blocks in early germ cell development, but in some cases elevation of temperature or lowering testosterone levels can overcome this block. This suggests that the low scrotal temperatures and high intratesticular testosterone may not be optimal for spermatogonial and spermatocyte development in these pathological cases, and that effects restorative of testosterone suppression and elevated temperature might be mechanistically linked. We hypothesize that suppression of testosterone elevates testicular temperature, which then enhances general or specific metabolic events to overcome genetic or toxicant induced blocks. The juvenile spermatogonial depletion (jsd) mutant mouse is one model to study the mechanisms by which elevated temperature and hormone suppression can alleviate the block in spermatogonial differentiation. Jsd is a mutation in the Utp14b gene, which is involved in ribosomal RNA processing. Utp14b is a copy of the widely expressed (except spermatocytes) X linked Utp14a gene. Utp14b is mainly expressed in germ cells. We propose that in jsd mice, testosterone suppression leads to a gradual temperature increase, which restores ribosomal RNA processing by upregulating Utp14a in spermatogonia and/or spermatocytes. We will test between this model and alternatives with the following Specific Aims: (I) Determine whether testosterone suppression elevates testicular temperature in vivo, whether testosterone inhibits spermatogonial differentiation by acting on cells involved in temperature regulation, and whether temperature but not testosterone affects differentiation in vitro. (II) Determine if 18S ribosomal RNA processing is defective in both spermatogonia and spermatocytes of jsd mice at scrotal temperatures, and if processing is more efficient at body temperature. (III) Determine the specific or general metabolic processes that are altered by elevation of temperature to overcome the defects in germ cell differentiation. If temperature elevation restores 18S rRNA processing in jsd mice, then increases in Utp14a levels in germ cells will be examined as a specific compensatory mechanism. In addition, (IV) we will evaluate the application of testosterone suppression and elevated temperature to enhance spermatogonial development in irradiated mice, a toxicant induced model of hypospermatogenesis. These results will provide insight into the molecular mechanisms underlying aspects of temperature and androgen effects on spermatogenesis and reveal a direct mechanistic link between these two modulators. This information would significantly contribute to both our basic understanding of the biological mechanisms involved in spermatogenesis, and to possible treatments for oligospermia or azoospermia in men. Partial or complete blocks at the early stages of spermatogenesis results in low or zero sperm counts, a problem that appears to be increasing in men. Elucidation of the causes of such blocks and the mechanisms by which temperature elevation and hormone suppression can reverse them in experimental animal models could apply to treatment of genetically or environmentally caused male infertility in humans. Further, proof of our hypothesis that the effects of testosterone suppression and temperature elevation are mechanistically linked would lead to new insights and interpretations of published research.

描述（由申请人提供）：遗传缺陷或有毒物质暴露通常会导致早期生殖细胞发育受阻，但在某些情况下，升高温度或降低睾酮水平可以克服这种阻碍。这表明，在这些病理病例中，低阴囊温度和高睾丸内睾酮可能不是精原细胞和精母细胞发育的最佳选择，并且睾酮抑制的恢复作用和升高的温度可能在机制上相关。我们假设抑制睾酮会升高睾丸温度，从而增强一般或特定的代谢事件以克服遗传或毒物诱导的阻断。幼年精原细胞耗竭（jsd）突变小鼠是研究升高温度和激素抑制缓解精原细胞分化受阻机制的一种模型。 Jsd 是 Utp14b 基因的突变，该基因参与核糖体 RNA 加工。 Utp14b 是广泛表达（精母细胞除外）X 连锁 Utp14a 基因的副本。 Utp14b主要在生殖细胞中表达。我们提出，在 jsd 小鼠中，睾酮抑制会导致温度逐渐升高，从而通过上调精原细胞和/或精母细胞中的 Utp14a 来恢复核糖体 RNA 加工。我们将在该模型和替代模型之间进行测试，具体目标如下：（I）确定睾酮抑制是否会升高体内睾丸温度，睾酮是否通过作用于参与温度调节的细胞来抑制精原细胞分化，以及温度而不是睾酮是否会影响精原细胞的分化。体外。 (II) 确定 jsd 小鼠精原细胞和精母细胞在阴囊温度下 18S 核糖体 RNA 加工是否存在缺陷，以及在体温下加工是否更有效。 (III) 确定因温度升高而改变的特定或一般代谢过程，以克服生殖细胞分化的缺陷。如果温度升高恢复了 jsd 小鼠的 18S rRNA 加工，那么生殖细胞中 Utp14a 水平的增加将被视为一种特定的补偿机制。此外，（IV）我们将评估睾酮抑制和升高温度的应用，以增强受辐射小鼠的精原细胞发育，这是一种毒物诱导的精子发生不足的模型。这些结果将深入了解温度和雄激素对精子发生影响的分子机制，并揭示这两种调节剂之间的直接机制联系。这些信息将极大地有助于我们对精子发生的生物学机制的基本理解，以及男性少精子症或无精子症的可能治疗。 精子发生早期阶段的部分或完全阻断会导致精子数量低或为零，这一问题在男性中似乎越来越严重。阐明这种阻塞的原因以及在实验动物模型中温度升高和激素抑制可以逆转它们的机制可以应用于治疗遗传或环境引起的人类男性不育症。此外，证明我们的假设，即睾酮抑制和体温升高的影响在机制上是相关的，这将为已发表的研究带来新的见解和解释。