Defining the mechanisms of temperature sensitive meiotic chromosome structures in male infertility

定义男性不育中温度敏感的减数分裂染色体结构的机制

• 批准号: 10507710
• 负责人: Cori K Cahoon
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507710
• 关键词: Address; Affect; Biological Models; Body Temperature; Caenorhabditis elegans; Cell Nucleus; Chromosome Structures; Chromosome abnormality; Chromosomes; Comparative Study; Congenital Abnormality; DNA Damage; Data; Defect; Developmental Process; Exhibits; Exposure to; Failure; Fertility; Fertility Disorders; Foundations; Gene Expression Profile; Generations; Genetic Recombination; Genome; Germ; Germ Cells; Goals; Haploidy; Heat Stress Disorders; Homologous Gene; Human; Infertility; Link; Male Infertility; Malignant Neoplasms; Malignant neoplasm of testis; Mammals; Meiosis; Meiotic Prophase I; Molecular; Mutation; Nature; Oocytes; Oogenesis; Organism; Outcome Study; Phenotype; Predisposition; Process; Protein Dynamics; Proteins; Proteomics; Reproduction; Reproductive Health; Resistance; Risk; Role; Sex Differences; Spermatocytes; Spermatogenesis; Spontaneous abortion; Stress; Structure; Synaptonemal Complex; Temperature; Work; biological adaptation to stress; cancer risk; egg; experience; experimental study; genetic information; genome integrity; insight; kinetosome; male; male fertility; microscopic imaging; next generation; novel; protein complex; response; sex; sexual dimorphism; sperm cell

PROJECT SUMMARY Sexually reproducing organisms faithfully transmit their genome to the next generation via haploid gametes, such as eggs and sperm. In contrast to oogenesis and other developmental processes, spermatogenesis must occur 2-7ºC below basal body temperature. Failure to precisely thermoregulate spermatogenesis or exposure to elevated temperatures are strongly linked to male infertility and an increased risk of testicular cancer, but the mechanisms behind temperature induced male infertility and cancer are unknown. Similar to mammals, Caenorhabditis elegans displays elevated levels of DNA damage and fertility defects in spermatogenesis following heat exposure. Notably, I have found in C. elegans that the synaptonemal complex (SC), a meiotic chromosome structure essential for fertility, is altered following heat exposure in only spermatocytes. In addition, I also uncovered that the SC is sexually dimorphic without heat exposure with spermatogenesis having differences in both SC protein composition and turnover compared to oogenesis. Here, I hypothesize that sexual dimorphisms in the SC contribute to the mechanism(s) causing temperature induced male infertility. In the proposed work, I will exploit the ease to access, manipulate, and visualize both spermatogenesis and oogenesis in the model system C. elegans to dissect the sexually dimorphic nature of the SC and address how these sex-specific differences contribute to heat induced male infertility. I will investigate whether differences in SC organization and composition during spermatogenesis render it temperature sensitive (Aim 1). These experiments will determine how heat affects both the ultrastructure and dynamics of the SC and other meiotic chromosome structures during spermatogenesis and oogenesis. In addition, the response of spermatocytes to heat exposure is variable with nuclei displaying two phenotypes: (1) sensitized nuclei, high levels of DNA damage and substantial SC defects, and (2) resistant nuclei, significantly less DNA damage and intact SC. To understand this nucleus autonomous response to heat, I will determine how the transcriptional profiles are changing within the sensitized and resistant spermatocyte nuclei and assess how loss of the SC influences the heat stress response of oocytes and spermatocytes (Aim 2). Finally, I will identify and characterize novel spermatogenesis proteins that cause SC heat sensitivity (Aim 3). Together, this study will illuminate, how temperature affects genome integrity in spermatocytes and identify the molecular mechanisms that underlie temperature associated infertility and cancer risk in male reproductive health.

项目摘要 有性繁殖的生物通过单倍体配子忠实地将它们的基因组传递给下一代， 比如卵子和精子。与卵子发生和其他发育过程相反，精子发生必须 发生在基础体温以下2-7ºC。无法精确调节精子发生或暴露 温度升高与男性不育和睾丸癌风险增加密切相关，但 温度引起的男性不育和癌症的机制尚不清楚。与哺乳动物相似， 秀丽隐杆线虫在精子发生中表现出高水平的DNA损伤和生育缺陷 热暴露后。值得注意的是，我发现在C。联会复合体（SC），一个减数分裂 染色体结构对生育力至关重要，在热暴露后仅在精母细胞中发生改变。在 此外，我还发现，在没有热暴露的情况下，SC具有性二态性，并伴随着精子发生 与卵子发生相比，SC蛋白质组成和周转都有差异。我假设 SC的性二型性参与了温度诱导雄性不育的机制。 在拟议的工作中，我将利用容易访问，操作，和可视化精子发生和 模型系统的卵子发生C. elegans解剖SC的性二态性，并解决如何 这些性别特异性差异导致热诱导的男性不育。我将调查是否存在差异， 精子发生过程中SC的组织和组成使其对温度敏感（目的1）。这些 实验将确定热如何影响SC和其他减数分裂的超微结构和动力学， 精子发生和卵子发生过程中的染色体结构。此外，精母细胞对 热暴露是可变的，细胞核显示两种表型：（1）致敏细胞核，高水平的DNA 损伤和实质性SC缺陷，和（2）抗性核，显著较少的DNA损伤和完整的SC。 了解这种细胞核对热的自主反应，我将确定转录谱是如何 在致敏和抗性精母细胞核内的变化，并评估SC的损失如何影响 卵母细胞和精母细胞的热应激反应（目的2）。最后，我将确定和表征小说 引起SC热敏感性的精子发生蛋白（Aim 3）。总之，这项研究将阐明， 温度影响精母细胞的基因组完整性，并确定其分子机制 男性生殖健康中与温度相关的不育和癌症风险。