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

基本信息

批准号：
10693975
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
项目类别：
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/10693975
关键词：
Ablation 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 Mus Mutation Nature Oocytes Oogenesis Organism Outcome Phenotype Predisposition Process Protein Dynamics Proteins Proteomics Reproduction Reproductive Health Resistance Risk Role Sex Differences Spermatocytes Spermatogenesis Spontaneous abortion Stress Structure Synaptonemal Complex Temperature Visualization 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 transmission process

项目摘要

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.

项目概要有性生殖的生物通过单倍体配子忠实地将其基因组传递给下一代，例如卵子和精子，与卵子发生和其他发育过程相反，精子发生必须。发生在低于基础体温 2-7°C 的情况下，无法精确调节精子发生或暴露的温度。气温升高与男性不育和睾丸癌风险增加密切相关，但与哺乳动物类似，温度导致男性不育和癌症背后的机制尚不清楚。秀丽隐杆线虫在精子发生过程中表现出较高水平的 DNA 损伤和生育缺陷值得注意的是，我在秀丽隐杆线虫中发现了联会复合体（SC），一种减数分裂。对于生育能力至关重要的染色体结构仅在精母细胞受热后发生改变。此外，我还发现，在没有热暴露的情况下，SC 在精子发生过程中是两性异形的与卵子发生相比，SC 蛋白质组成和周转率存在差异。 SC 的性别二态性有助于导致温度引起的男性不育的机制。在拟议的工作中，我将利用访问、操作和可视化精子发生和线虫模型系统中的卵子发生剖析了 SC 的性二态性并解决了如何这些性别特异性差异是否会导致热引起的男性不育。精子发生过程中的 SC 组织和组成使其对温度敏感（目标 1）。实验将确定热量如何影响 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，精母细胞对的反应。热暴露随细胞核表现出两种表型而变化：(1) 敏化细胞核，高水平 DNA (2)抗性细胞核，DNA损伤明显减少，SC完好。这个细胞核对热的自主反应，我将确定转录谱是如何的敏感和耐药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（目标 2）最后，我将识别并表征新的。这项研究将共同阐明导致 SC 热敏感性的精子发生蛋白（目标 3）。温度影响精母细胞基因组完整性并确定其背后的分子机制温度与男性生殖健康中的不育和癌症风险相关。