Androgens: unlocking the key drivers of male health and wellbeing

男性的健康和幸福是睾酮依赖。低循环睾酮浓度与发展慢性和年龄相关疾病的风险增加有关，如肥胖，糖尿病和心脏病。然而，迄今为止，因果关系尚未建立，因此无法为这些男性提供个性化治疗。睾酮替代疗法通常用于睾酮水平低的男性，在许多情况下可以改善症状，然而，这并非没有争议，最近的几项临床试验表明，治疗可能会增加心脏病发作和中风的风险，并增加前列腺癌的侵袭性。这使我们处于一个具有挑战性的位置，低睾酮和睾酮替代疗法都与不良临床结局相关。在成年男性中，95%的循环睾酮是由睾丸内的特化Leydig细胞产生的，因此睾丸代表了身体的“睾酮工厂”。这项研究的目的是提供支持这些Leydig细胞的发育和维持的自然过程的基本理解，以支持整个生命的最佳睾酮水平，因为证据表明这是对终身男性健康的最佳保护。我们还将开发和测试新的疗法，可以支持或增强睾丸的睾酮生产，作为替代睾酮替代疗法。建立一个健康的睾酮概况：睾丸间质细胞在成年后形成一个稳定的群体，在整个生命过程中数量几乎没有变化。如果我们要制定策略来支持或增加男性睾丸激素的产生，那么了解功能齐全的Leydig细胞群体是如何发展的是至关重要的。我们将研究Leydig细胞群的起源，并确定睾丸内的其他细胞和激素如何相互作用，以促进和支持Leydig细胞群的发育。通过这一过程，我们不仅将产生理解，而且还确定可以操纵，以改善Leydig细胞发育或功能的因素。在整个生命中保持健康的睾丸激素概况：在成年生活中减少睾丸激素的产生无疑与病理有关。了解原因/后果关系，并确定在整个成年期保留和功能支持Leydig细胞群的方法，对于促进终身男性健康至关重要。我们将产生早衰的转基因小鼠模型，以了解衰老对睾丸睾酮生产机制的影响，以及如何在整个生命过程中保持健康的睾酮水平。我们还将确定肥胖和糖尿病如何抑制睾丸睾酮的产生，并确定克服这一点的方法。修复，再生或取代Leydig细胞群：为了开发新的疗法，可以支持或增强睾丸睾酮的产生，我们将修改病毒，将新的遗传物质直接传递到睾丸细胞。这种方法将使我们能够修改或消除基因的功能，以了解其在正常条件下的作用。我们还将在基因治疗方法中使用该系统，以提供支持或改善睾丸睾酮产生的基因。在第二种方法中，我们将确定特异性杀死Leydig细胞群的方法，正如我们从大鼠研究中所知，这样做会导致新的年轻Leydig细胞群的再生。最后，在第三种方法中，我们将直接将新细胞注射到睾丸中，我们相信这将支持或改善睾酮的产生。这项研究将提供对健康的终身睾酮特征的机制的详细了解，并释放睾丸“睾酮工厂”的潜力，以支持男性的终身睾酮。

Male health and wellbeing is testosterone dependent. Low circulating testosterone concentration is linked to an increased risk of developing chronic and age-related conditions, such as obesity, diabetes and heart disease. However, to date, the cause/consequence relationship has not been established, making it impossible to provide personalised therapy for these men. Testosterone replacement therapy is commonly used in men with low testosterone, and can improve symptoms in many cases, however, this is not without controversy, with several recent clinical trials suggesting treatment may increase risk of heart attacks and strokes, and increase the aggressiveness of prostate cancers. This places us the challenging position where both low testosterone and testosterone replacement therapy are associated with negative clinical outcomes. In adult men 95% of circulating testosterone is produced by specialised Leydig cells within the testes, as such the testis represents the body's 'testosterone factory'. The purpose of this research is to provide a fundamental understanding of the natural processes that support the development and maintenance of these Leydig cells, to support an optimal testosterone profile throughout life, as evidence suggests that this is the best protection for lifelong male health. We will also develop and test new therapies that can support or enhance testosterone production by the testis, as an alternative to testosterone replacement therapy.Establishing a healthy testosterone profile: Leydig cells form a stable population in adulthood, barely changing in number throughout life. Understanding how a population of fully functioning Leydig cell develops is essential if we are to develop strategies to support or increase testosterone production in men where it is suboptimal. We will investigate the origin of the Leydig cell population and determine how other cells and hormones within the testis interact to promote and support the development of the Leydig cell population. Through this process, we will not only generate understanding, but also identify factors that can be manipulated to improve Leydig cell development or function.Maintaining a healthy testosterone profile throughout life: Reduced testosterone production in adult life is unquestionably linked to pathologies. Understanding the cause/consequence relationships and identifying ways to retain and functionally support the Leydig cell population throughout adulthood is essential for promotion of lifelong male health. We will generate transgenic mouse models of premature ageing, to understand the impacts of ageing on the testosterone production machinery of the testis, and how a healthy testosterone profile can be maintained throughout life. We will also determine how obesity and diabetes suppress testicular testosterone production and identify approaches to overcome this.Repair, regenerate or replace the Leydig cell population: To develop new therapies that can support or enhance testosterone production by the testis, we will modify viruses to deliver new genetic material directly to cells of the testis. This approach will allow us to modify or ablate the function of a gene in order to understand its role under normal conditions. We will also use this system in a gene therapy approach, to deliver genes that will support or improve testosterone production by the testis. In a second approach, we will identify ways of specifically killing the Leydig cell population, as we know from rat studies that doing so leads to regeneration of a new, youthful Leydig cell population. Finally, in a third approach, we will inject new cells directly into the testis, which we believe will support or improve testosterone production.This Research will provide a detailed understanding of the mechanisms underpinning a healthy lifelong testosterone profile, and unlock the potential of the testicular 'testosterone factory' to support this in men throughout life.