Impact of peroxisomal metabolism in germ and Leydig cells on overall testis functions and male fertility

生殖细胞和间质细胞中过氧化物酶体代谢对整体睾丸功能和男性生育能力的影响

• 批准号: 209584397
• 负责人: Professor Dr. Georg Lüers
• 金额: --
• 依托单位: Institut für Anatomie and Experimentelle Morphologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/209584397?language=en
• 关键词: Impact; peroxisomal; metabolism; germ; Leydig

Human disorders with peroxisomal deficiency show a range of testicular pathologies leading to male infertility, the molecular pathogenesis of which is not yet understood. We have therefore characterised peroxisomes and identified a strong heterogeneity of peroxisomal protein composition in distinct cell types of mouse and human testis and revealed that Sertoli cell peroxisomes are essential for the maintenance of regular spermatogenesis and the overall regulation of gonadal steroid metabolism. Since the impact of peroxisomal metabolism of germ and Leydig cells on overall testicular functions is not yet understood, we will establish PEX13KO-mouse models with peroxisome deficiency to investigate the relevance of peroxisomal metabolism 1) in spermatogonia and spermatids for germ cell differentiation and for male fertility, and 2) in Leydig cells for androgen synthesis, paracrine and endocrine control of testicular functions. The phenotypic analyses will include the histopathological characterisation of testis samples, analysis of marker enzymes, biochemical measurements of steroids and other peroxisome-related metabolites, mRNAexpression profiling and in vitro studies on organotypic and primary cell cultures. 3) Important results will be transferred to the analyses of human testis and blood samples.

人类疾病与过氧化物酶体缺乏症显示一系列睾丸病理导致男性不育，其分子发病机制尚不清楚。因此，我们对过氧化物酶体进行了表征，并在小鼠和人类睾丸的不同细胞类型中发现了过氧化物酶体蛋白质组成的强烈异质性，并揭示了支持细胞过氧化物酶体对于维持正常的精子发生和性腺类固醇代谢的整体调节至关重要。由于生殖细胞和间质细胞的过氧化物酶体代谢对睾丸整体功能的影响尚不清楚，我们将建立过氧化物酶体缺乏的pex13ko小鼠模型，研究1)精原细胞和精细胞的过氧化物酶体代谢与生殖细胞分化和男性生殖能力的关系，以及2)间质细胞的过氧化物酶体代谢与雄激素合成、旁分泌和内分泌控制睾丸功能的关系。表型分析将包括睾丸样本的组织病理学特征、标记酶的分析、类固醇和其他过氧化物酶体相关代谢物的生化测量、mrna表达谱以及器官型和原代细胞培养的体外研究。3)重要的结果将转移到人类睾丸和血液样本的分析。