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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：
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
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/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

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.

项目总结