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

类固醇激素醛固酮通过控制钠滞留来调节血压。所有已知的单基因高血压病症都与醛固酮或钠重吸收有关，这一事实突显了这种激素在血压控制中的重要作用。醛固酮的工作原理是激活细胞内的一种“受体”蛋白，进而开启特定的基因。这些基因的产物会产生钠滞留。这种受体的拮抗剂(阻滞剂)用于治疗高血压，但有不良的副作用。新的、更具体的拮抗剂的设计一直很缓慢，因为我们不知道这些药物是如何与受体结合的，以及它们对蛋白质有什么影响。人们对醛固酮受体的功能知之甚少。该项目旨在对受体进行详细研究。我们正在确定受体结构中对激素结合至关重要的区域。这些信息对设计新的拮抗剂至关重要。醛固酮受体的不同寻常之处在于，它还被皮质醇激活，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，有可能确定这两种类固醇是否以相同的方式激活受体。如果不彻底研究受体本身，就不可能理解天然激素和合成拮抗剂是如何发挥作用的。我们打算研究醛固酮受体功能的基本方面。特别是，我们希望识别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，对解释天然激素和合成拮抗剂的作用至关重要。这些实验的结果将促进我们对醛固酮作用的基本生物学及其在心血管生物学中的作用的理解，并导致设计出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.