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

人类过氧化物酶体缺乏症表现出一系列导致男性不育的睾丸病理，其分子发病机制尚不清楚。因此，我们已经确定了过氧化物酶体的特点，并确定了一个强大的异质性的过氧化物酶体蛋白质组成的不同类型的小鼠和人类睾丸，并透露，支持细胞过氧化物酶体是必不可少的维持正常的精子发生和性腺类固醇代谢的整体调节。由于尚未了解生殖细胞和间质细胞的过氧化物酶体代谢对整体睾丸功能的影响，因此我们将建立过氧化物酶体缺乏的PEX13 KO小鼠模型，以研究1）精原细胞和精子细胞中过氧化物酶体代谢与生殖细胞分化和雄性生育力的相关性，以及2）间质细胞中过氧化物酶体代谢与睾丸功能的雄激素合成、旁分泌和内分泌控制的相关性。表型分析将包括睾丸样本的组织病理学表征、标记酶分析、类固醇和其他过氧化物酶体相关代谢物的生化测量、mRNA表达谱分析以及器官型和原代细胞培养物的体外研究。3)重要结果将转移到人睾丸和血液样本的分析中。

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.