Androgens: unlocking the key drivers of male health and wellbeing

男性的健康和幸福依赖于睾丸激素。低循环睾酮浓度与患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，到目前为止，因果关系尚未确定，因此不可能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，最近的一些临床试验表明，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。这给我们带来了一个挑战，低睾酮和睾酮替代疗法都与负面的临床结果有关。在成年男性中，95%的循环睾酮是由睾丸内专门的间质细胞产生的，因此睾丸代表着人体的“睾酮工厂”。这项研究的目的是提供对支持这些间质细胞发育和维持的自然过程的基本理解，以支持一生中最佳的睾酮水平，因为有证据表明这是终身男性健康的最佳保护。我们还将开发和测试新的治疗方法，以支持或提高睾丸激素的产生，作为睾丸激素替代疗法的替代方案。建立健康的睾丸激素档案：间质细胞在成年期形成一个稳定的种群，在一生中几乎没有变化。了解一群功能齐全的间质细胞是如何发育的，如果我们要制定策略来支持或增加男性睾酮的分泌，这是至关重要的。我们将研究睾丸间质细胞群的起源，并确定睾丸内其他细胞和激素如何相互作用以促进和支持睾丸间质细胞群的发育。通过这一过程，我们不仅将产生理解，而且还将确定可以操纵的因素，以改善间质细胞的发育或功能。在一生中保持健康的睾酮水平：成年后睾酮水平的降低无疑与疾病有关。了解因果关系，确定在成年期保留和功能支持间质细胞群的方法，对于促进男性终身健康至关重要。我们将产生早衰的转基因小鼠模型，以了解衰老对睾丸激素生产机制的影响，以及如何在一生中保持健康的睾丸激素水平。我们还将确定肥胖和糖尿病如何抑制睾丸睾酮的产生，并确定克服这一问题的方法。修复、再生或替换睾丸间质细胞群：为了开发新的疗法，支持或增强睾丸激素的产生，我们将修改病毒，将新的遗传物质直接传递到睾丸细胞中。这种方法将允许我们修改或去除基因的功能，以便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，以传递支持或改善睾丸激素产生的基因。在第二种方法中，我们将确定特异性杀死间质细胞群的方法，正如我们从老鼠研究中知道的那样，这样做会导致新的、年轻的间质细胞群的再生。最后，在第三种方法中，我们将把新的细胞直接注入睾丸，我们相信这将支持或改善睾丸激素的产生。这项研究将详细了解支撑健康的终身睾酮水平的机制，并解锁睾丸“睾酮工厂”的潜力，以支持男性一生的睾酮水平。

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.