Molecular characterisation of the ligand-binding domain of the mineralocorticoid receptor

类固醇激素醛固酮通过控制钠潴留来调节血压。这种激素在血压控制中的重要作用被所有已知的单基因高血压疾病都涉及醛固酮或钠重吸收的事实所强调。醛固酮通过激活细胞内的“受体”蛋白来发挥作用，而这种蛋白反过来又会开启特定的基因。这些基因的产物产生钠潴留。该受体的拮抗剂（阻断剂）用于治疗高血压，但具有不期望的副作用。新的、更特异的拮抗剂的设计一直很缓慢，因为我们不知道这些药物如何与受体结合，以及它们对蛋白质有什么影响。醛固酮受体如何发挥作用还知之甚少。本项目旨在详细研究该受体。我们正在确定对激素结合很重要的受体结构区域。这些信息对于设计新的拮抗剂至关重要。醛固酮受体是不寻常的，因为它也被皮质醇激活，皮质醇是一种与压力和炎症有关的类固醇激素。通过检查激素结合，可以确定这两种类固醇是否以相同的方式激活受体。如果不对受体本身进行彻底的研究，就不可能了解天然激素和合成拮抗剂的功能。我们打算研究醛固酮受体功能的基本方面。特别是，我们希望鉴定与受体相互作用的蛋白质。这些蛋白质增强或抑制受体开启基因的能力，对于解释天然激素和合成拮抗剂的作用至关重要。从这些实验的结果应该推进我们的理解的基础生物学的醛固酮的行动和它在心血管生物学中的作用，并导致设计更好的受体拮抗剂用于治疗高血压和心脏纤维化。

The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The important role of this hormone in blood pressure control is underlined by the fact that all known monogenetic hypertensive conditions involve aldosterone or sodium reabsorption. Aldosterone works by activating an intracellular 'receptor' protein that in turn switches on specific genes. The products of these genes act to produce sodium retention. Antagonists (blockers) of this receptor are used in the treatment of hypertension but have undesirable side effects. The design of new, more specific, antagonists has been slow because we do not understand how these drugs bind to the receptor and what effect they have on the protein. How the aldosterone receptor functions is poorly understood. This project aims to investigate the receptor in detail. We are in the process of determining regions of the receptor structure important for hormone binding. This information is vital for the design of new antagonists. The aldosterone receptor is unusual in that it is also activated by cortisol, a steroid hormone involved in stress and inflammation. By examining hormone binding it may be possible to determine if the two steroids activate the receptor in the same way. An understanding of how both natural hormones and synthetic antagonists function is impossible without thorough study of the receptor itself. We intend to examine fundamental aspects of aldosterone receptor function. In particular we wish to identify proteins that interact with the receptor. These proteins either enhance or inhibit the ability of the receptor to switch on genes and are vital to explaining the actions of both natural hormones and synthetic antagonists. Results from these experiments should advance our understanding of the basic biology of aldosterone action and its role in cardiovascular biology, and lead to the design of better receptor antagonists for use in the treatment of hypertension and cardiac fibrosis.