The roles of glucocorticoids and catecholamines for the testis and peritubular cells

人睾丸小管周围细胞（HTPCs）表达糖皮质激素受体（GR; NR3C1）和儿茶酚胺受体（包括α 1； ADRA1）。这暗示了这些激素的作用，然而，这些作用到今天还没有得到很好的定义。这个话题引起了人们的兴趣，因为越来越清楚的是，在不同形式的压力下，人类糖皮质激素（GC）和儿茶酚胺水平的升高与睾丸功能和生育能力受损有关。根据我们之前和我们的初步数据，我们假设这部分是由睾丸水平的gc和儿茶酚胺的直接作用介导的，特别是在小管周围细胞的水平。小管周围细胞可以从人类、非人类灵长类动物和小鼠的睾丸中分离出来，并与器官型培养物一起作为进入睾丸的实验窗口。从先前使用人类TPCs的研究中可以清楚地看出，它们对睾丸功能的许多方面都很重要，因为它们运输精子，促进精原干细胞生态位和分泌因子，这些因子参与控制血管。此外，我们最近在人类TPCs中的数据表明，儿茶酚胺通过激活α 1受体，刺激促炎因子的分泌。我们的初步数据还表明，GR在人TPCs中的激活会改变其平滑肌表型、细胞外基质蛋白的产生并影响细胞因子的产生。因此，我们假设GC和儿茶酚胺对小管周围细胞的功能有重要影响，从而可能影响睾丸内稳态，从而影响生育和不育。我们建议结合三个实验室的专业知识，在一项以人类为中心的研究中，研究GR/ α 1受体相关信号在睾丸中的作用。我们将通过研究不同的发育状态、年龄和不育，获得关于睾丸中GR/ α 1受体的知识。由于这两种受体的主要表达在小管周围细胞中，我们将阐明它们在三个物种的分离TPCs和来自jacchus Callithrix的永生化非人灵长类TPCs中的功能作用，这代表了一个翻译模型。非人类灵长类动物睾丸和小鼠片段的离体研究将补充实验。此外，我们计划采用相关敲除小鼠模型。我们期望详细的功能研究、转录组学和蛋白质组学分析的结果将使我们能够破译GCs和儿茶酚胺在睾丸中的作用。

Human testicular peritubular cells (HTPCs) express the receptors for glucocorticoids (GR; NR3C1) and the receptors for catecholamines (including alpha 1; ADRA1). This implies actions of these hormones, which are however to this day not well defined. This topic has gained interest, because it is becoming clear that elevated levels of glucocorticoids (GC) and catecholamines during different forms of stress in man are being associated with impaired testicular functions and fertility. Based on our previous and our preliminary data, we postulate that this is mediated, in part, by direct actions of GCs and catecholamines at the level of the testis and specifically at the level of the peritubular cell. Peritubular cells can be isolated from the human, nonhuman primate and mouse testis and together with organotypic cultures they serve as experimental windows into the testis. It has become clear from the previous study using human TPCs that they are important for many aspects of testicular functions, as they transport sperm, contribute to the spermatogonial stem cell niche and secrete factors, which are involved in the control of blood vessels. In addition, our recent data in human TPCs show that catecholamines, via activation of the alpha 1 receptors, stimulate the secretion of pro-inflammatory factors. Our preliminary data also show that activation of GR in human TPCs entails changes in their smooth muscle phenotype, extracellular matrix proteins production and influences cytokine production. Hence we hypothesize that GC and catecholamines have a crucial influence on the functions of peritubular cells, and thereby they may affect testicular homeostasis and consequently fertility and infertility. We propose to examine the testicular roles of GR/alpha 1 receptor-related signaling in a human-focused study by combining the expertise of three laboratories. We will gain knowledge about GR/ alpha 1 receptors in the testis, by studying different states of development, age and infertility. Since a predominant expression of both receptors is seen in peritubular cells, we will elucidate their functional roles in isolated TPCs from three species and in immortalized nonhuman primate TCPs from Callithrix jacchus, which represents a translational model. Ex vivo studies in nonhuman primate testes and mouse fragments will complement the experiments. In addition, we plan to employ relevant knockout mouse models. We expect that the results of the detailed functional studies, transcriptomic and proteomic analyses will enable us to decipher the testicular roles of GCs and catecholamines.