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.

项目总结 有性繁殖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 比基础体温低2-7摄氏度。未能对精子发生或暴露进行精确的温度调节 体温升高与男性不育症和睾丸癌风险增加密切相关，但 温度导致男性不育和癌症背后的机制尚不清楚。与哺乳动物相似， 秀丽线虫在精子发生中DNA损伤和生育缺陷水平升高 在热暴露之后。值得注意的是，我发现线虫的联会复合体(SC)是一种减数分裂 只有精母细胞受热暴露后，才会改变生育所必需的染色体结构。在……里面 此外，我还发现SC是性二型的，没有受热与精子发生的关系 与卵子发生相比，在SC蛋白组成和周转方面都有差异。在这里，我假设 认为SC中的性二型与温度导致男性不育的机制有关(S)。 在拟议的工作中，我将利用访问、操作和可视化精子发生和 秀丽线虫模型系统中的卵子发生，以剖析SC的性二型性本质并解决如何 这些性别差异导致了高温导致的男性不育。我将调查是否存在差异 干细胞在精子发生过程中的组织和组成使其对温度敏感(目标1)。这些 实验将确定高温如何影响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，细胞核表现出两种表型：(1)致敏的细胞核，高水平的DNA 损伤和大量SC缺陷；(2)抗核，显著减少DNA损伤和完整SC。至 理解这个核对热的自主反应，我将确定转录图谱是如何的 在致敏和耐药精母细胞核内的变化，并评估SC的丢失如何影响 卵母细胞和精母细胞的热应激反应(目标2)。最后，我将对小说进行鉴定和刻画 导致SC热敏感的精子发生蛋白(目标3)。总而言之，这项研究将阐明， 温度影响精母细胞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症和癌症风险。