Interrogating the role of SGPL1 in adrenal/gonadal development and acute steroidogenesis

SGPL 1基因缺陷与影响肾上腺、肾脏、神经系统和皮肤的罕见疾病有关。受影响的儿童有减少SGPL 1，一个重要的脂质系统的关键酶，鞘脂，这是存在于整个身体。鞘脂在体内具有许多重要功能，较小的鞘脂在信号传导中起作用，而较大的鞘脂形成身体细胞的重要组成部分。SGPL 1的缺乏导致系统中的阻塞，可能导致某些鞘脂积聚。我们小组主要研究肾上腺疾病的遗传原因。肾上腺产生皮质醇，这是一种重要的类固醇激素，在身体和情绪紧张时维持身体的适当反应。相当比例的SGPL 1缺乏症患者肾上腺功能异常，此外，三分之一的男性患者也有睾丸功能异常。睾丸还产生一种类固醇激素，睾丸激素。因此，患者表现为睾丸激素产生受损和性发育障碍。我将进行一系列细胞实验，试图了解肾上腺和睾丸中的疾病机制，以加速发现新的治疗靶点。在这个项目中，我将研究SGPL 1缺乏如何影响鞘脂在人肾上腺细胞模型和SGPL 1缺乏的小鼠睾丸细胞模型中的积累（目前还没有等效的人类模型）。肾上腺和睾丸细胞中类固醇激素的产生依赖于共同的生物过程。我将使用这两个模型来评估鞘脂代谢紊乱如何影响已知在类固醇激素产生中起关键作用的信号通路。鞘脂也可能在肾上腺和睾丸的发育中发挥重要作用，我们的患者在出生后不久就出现了非常早期的疾病表现。目前的工作集中在SGPL 1缺陷小鼠模型中SGPL 1对胎鼠肾上腺和睾丸发育的影响。在这个项目中，我将首次与我们的合作者一起使用三维人类胎儿肾上腺模型来评估SGPL 1缺乏对人类胎儿肾上腺类固醇产生能力的影响。同样，我将使用三维人类胎儿睾丸模型来进一步研究SGPL 1缺乏不仅对人类睾丸的类固醇激素产生细胞，而且对负责生育的细胞群的影响。虽然睾丸疾病可以在我们的一些患者的早期生活中出现，但疾病也可能随着时间的推移而发展。这些研究将有助于为受影响患者的临床筛查提供信息，以评估对激素补充的需求和对未来生育能力的考虑。虽然罕见，但SGPL 1缺乏症非常虚弱，并可能显着影响预期寿命。了解肾上腺和睾丸疾病的发病机制可能至关重要，可以深入了解哪些生物途径可能在其他受影响的身体系统中被破坏，例如肾脏和神经系统。重要的是，鞘脂途径易于治疗操作，这项工作将加速发现肾上腺和睾丸疾病治疗的新治疗靶点。此外，由于在几种疾病的治疗中正在探索改变SGPL 1活性的策略，因此了解这种遗传缺陷对人类疾病的影响将为改变这种脂质系统的潜在影响提供重要见解。

Defects in the gene, sphingosine-1-phosphate lyase, SGPL1 are associated with a rare disease affecting the adrenal glands, kidneys, neurological system and skin. Affected children have a reduction in SGPL1, a key enzyme of an important lipid system, the sphingolipids, which are present throughout the body. Sphingolipids have many important functions in the body, smaller sphingolipids have a role in signalling whilst larger sphingolipids form important components of the body's cells. Deficiency of SGPL1 results in a block in the system, likely to cause certain sphingolipids to accumulate. Our group primarily investigates inherited causes of adrenal disease. The adrenal glands produce cortisol, an essential steroid hormone in maintaining the body's appropriate response during times of physical and emotional stress. A significant proportion of patients with SGPL1 deficiency have abnormal adrenal function, furthermore, a third of male patients with the condition also have abnormal testicular function. The testes also produce a steroid hormone, testosterone. Patients as a consequence present with impaired testosterone production and disorders of sexual development. I will be conducting a range of cell experiments to try and understand the disease mechanism in the adrenals and testes, to hasten discovery of new therapeutic targets. In this project I will investigate how SGPL1 deficiency affects sphingolipid accumulation in a human adrenal cell model and a mouse testis cell model deficient in SGPL1 (an equivalent human model is not currently available). Steroid hormone production in adrenal and testicular cells relies on common biological processes. I will be using these two models to assess how the disturbance of sphingolipid metabolism affects signalling pathways known to be key in steroid hormone production. Sphingolipids may also play a significant role in the development of the adrenal and testis as evidenced by the very early disease presentations of our patients soon after birth. Current work is focused on the effect of SGPL1 on foetal mouse adrenal and testicular development in an SGPL1 deficient mouse model. In this project for the first time, together with our collaborators, I will be using a 3-dimensional human foetal adrenal model to assess the effect of SGPL1 deficiency on the steroid producing abilities of the human foetal adrenal. Similarly, I will use a 3-dimensional human foetal testis model to further investigate the impact of SGPL1 deficiency not only on the steroid hormone producing cells of the human testis but also the cell populations responsible for fertility. Whilst testicular disease can present in early life for some of our patients, it is also possible that disease can develop over time for others. These studies will help inform the clinical screening for affected patients to assess the need for hormone supplementation and consideration of future fertility. Whilst rare, SGPL1 deficiency is extremely debilitating and can significantly affect life expectancy. Understanding the disease mechanism in the adrenal and testicular condition may crucially provide insights into which biological pathways may be disrupted in other body systems affected, for instance the kidneys and nervous system. The sphingolipid pathway is, importantly, amenable to therapeutic manipulation and this work will hasten the discovery of new therapeutic targets for treatment in adrenal and testicular disease. Furthermore, as strategies to modify the activity of SGPL1 are being explored in therapies for several conditions, understanding the impact of this genetic defect in human disease will provide important insights into the potential effects of altering this lipid system.