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

人睾丸小管周围细胞表达糖皮质激素受体(GR；NR3C1)和儿茶酚胺受体(包括α1；ADRA1)。这意味着这些荷尔蒙的作用，然而，到目前为止还没有很好的定义。这个话题引起了人们的兴趣，因为越来越明显的是，在不同形式的压力下，男性体内糖皮质激素(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。根据我们以前和我们的初步数据，我们假设这在一定程度上是由GCs和儿茶酚胺在睾丸水平，特别是在小管周细胞水平上的直接作用所介导的。可以从人、非人灵长类动物和小鼠的睾丸中分离出管周细胞，并与器官培养一起作为进入睾丸的实验窗口。以前使用人类TPC的研究已经清楚地表明，它们对睾丸功能的许多方面都很重要，因为它们运输精子，促进精原干细胞巢和参与血管控制的分泌因子。此外，我们最近在人类TPC中的数据显示，儿茶酚胺通过激活α1受体，刺激促炎因子的分泌。我们的初步数据还表明，人TPC中GR的激活会导致其平滑肌表型、细胞外基质蛋白产生的变化，并影响细胞因子的产生。因此，我们推测GC和儿茶酚胺对肾小管周围细胞的功能有重要影响，因此它们可能影响睾丸的动态平衡，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检查GR/α1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、年龄和不育症来了解睾丸中的GR/α1受体。由于这两种受体主要在肾小管周细胞中表达，我们将阐明它们在三个物种分离的TPC中的功能作用，以及来自Callithrix Jacchus的永生化的非人类灵长类TCPs，这代表了一个翻译模型。对非人类灵长类动物睾丸和老鼠碎片的体外研究将补充实验。此外，我们还计划采用相关的基因敲除小鼠模型。我们期望详细的功能研究、转录和蛋白质组学分析的结果将使我们能够破译GC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.