Antioxidant defence in adrenocortical cells

氧化应激(OS)与许多人类疾病状态有关，包括神经退行性疾病、癌症、中风、糖尿病和心脏病。我们研究了一种名为家族性糖皮质激素缺乏症(FGD)的罕见疾病的患者，在这种疾病中，身体无法产生一种名为皮质醇的糖皮质激素。患有这种疾病的患者没有应对压力的机制。例如，如果他们的身体因疾病而变得紧张，他们的血糖水平会下降，他们容易受到感染，如果不治疗，他们可能会死亡。ACTH通过其受体起作用，是一种对压力做出反应的荷尔蒙，它会导致肾上腺细胞产生皮质醇。我们之前已经在这个途径中发现了导致FGD的三个基因的缺陷。最近，我们发现，通常与细胞抵御氧化应激有关的四个基因的缺陷也可以导致这种疾病。OS如何阻止皮质醇分泌的确切机制还不完全清楚，我们认为其他基因也可能参与其中。该项目旨在发现OS影响肾上腺细胞以阻止它们产生皮质醇的机制。我们也希望通过研究FGD患者的基因构成来发现这一途径中的其他基因。如果我们能发现OS是如何引起它的影响的，那么这可能会给我们提供线索，了解上面列出的其他疾病的机制，然后可能设计出减少它的药物。

Oxidative stress (OS) is involved in many human disease states including neurodegenerative diseases, cancer, stroke, diabetes and heart disease. We study patients with a rare disease called Familial Glucocorticoid Deficiency (FGD) in which the body fails to produce a glucocorticoid called cortisol. Patients with this disease do not have a mechanism to cope with stress. If their body becomes stressed, for example by illness, their blood sugar levels drop, they become liable to infections and they may die if untreated. ACTH, acting through its receptor, is the hormone that is produced in response to stress and it causes the cells of the adrenal gland to produce cortisol. We have previously found defects in three genes in this pathway that cause FGD. More recently we have discovered that defects in four genes usually associated with a cells defence against oxidative stress, can also cause the disease. Exactly how OS prevents cortisol secretion is not fully understood and we believe that other genes may also be involved. This project aims to discover the mechanism by which OS affects the cells of the adrenal to prevent them making cortisol. We also hope to find other genes in this pathway by studying the genetic make-up of FGD patients. If we can discover how the OS causes its effect then this might give us clues to the mechanism in other diseases like those listed above and it may then be possible to design drugs to reduce it.