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

糖皮质激素和儿茶酚胺对睾丸和管周细胞的作用

• 批准号: 427588170
• 负责人: Professor Dr. Rüdiger Behr
• 金额: --
• 依托单位: Deutsches Primatenzentrum GmbH - Leibniz-Institut für Primatenforschung (DPZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/427588170?language=en
• 关键词: roles; glucocorticoids; catecholamines; testis; peritubular

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.

人睾丸管周细胞（HTPC）表达糖皮质激素受体（GR; NR 3C 1）和儿茶酚胺受体（包括α 1; ADRA 1）。这意味着这些激素的作用，然而到今天还没有很好的定义。这个话题已经引起了人们的兴趣，因为越来越清楚的是，在男性不同形式的压力期间，糖皮质激素（GC）和儿茶酚胺水平升高与睾丸功能和生育能力受损有关。根据我们以前的和我们的初步数据，我们假设，这是介导的，在一定程度上，通过直接行动的GC和儿茶酚胺在睾丸的水平，特别是在管周细胞的水平。管周细胞可以从人、非人灵长类动物和小鼠睾丸中分离出来，并与器官型培养物一起作为睾丸的实验窗口。 从先前使用人TPC的研究中已经清楚地看出，它们对睾丸功能的许多方面都很重要，因为它们运输精子，有助于精原干细胞生态位和分泌参与血管控制的因子。此外，我们最近在人TPC中的数据表明，通过激活α 1受体，儿茶酚胺刺激促炎因子的分泌。我们的初步数据还表明，GR在人类TPC的激活需要在其平滑肌表型，细胞外基质蛋白的生产和影响细胞因子的生产的变化。因此，我们推测GC和儿茶酚胺对管周细胞的功能有着至关重要的影响，从而它们可能影响睾丸的稳态，从而影响生育和不育。我们建议通过结合三个实验室的专业知识，在以人为中心的研究中检查GR/α 1受体相关信号的睾丸作用。我们将通过研究不同的发育状态，年龄和不孕症来获得有关睾丸中GR/α 1受体的知识。由于这两种受体的主要表达被认为是在管周细胞中，我们将阐明其功能作用，从三个物种和永生化的非人灵长类TCPs从Callithrix jacchus，这是一个翻译模型中分离的TPC。 在非人灵长类动物睾丸和小鼠片段中的离体研究将补充实验。此外，我们计划采用相关的基因敲除小鼠模型。我们希望详细的功能研究，转录组学和蛋白质组学分析的结果将使我们能够破译GC和儿茶酚胺的睾丸作用。