In vivo and ex vivo lessons from somatic adrenal mutations in cell adhesion molecule 1 for physiological and pathological production of aldosterone

高血压（高血压）是一种常见的疾病，它增加了受影响个体发生严重健康并发症（包括肾衰竭和中风）的风险。在5-10%的病例中，高血压可归因于原发性醛固酮增多症（PA）。在这种情况下，肾上腺（位于腹部后部肾脏的顶部）中或两者的细胞发生突变（DNA中的“拼写错误”），导致血液中醛固酮水平过高。这会导致钠（盐）在体内滞留，并增加血压。PA比其他原因引起的高血压具有更高的心脏病风险，并有特定的治疗选择。据估计，目前，由于多种因素，只有不到1%的PA患者接受了研究和治疗。在大约一半的患者中，异常的激素水平来自一个肾上腺中的离散良性结节（肿瘤）;在另一半患者中，问题更加扩散并影响两个腺体。治疗方案包括手术或药物治疗，旨在对抗醛固酮的影响。指南建议，手术切除肾上腺是首选的治疗方法的情况下，过量的醛固酮主要是由一个，而不是两个腺体。识别此类患者涉及侵入性手术，需要特定的专业知识，手术后的结果是可变的。虽然一些患者的高血压被治愈，但其他患者没有受益或仅部分治愈。布朗教授和他的团队在研究PA方面拥有丰富的经验，其目标是使其更容易诊断和治疗;并选择合适的患者进行正确的治疗。某些突变似乎与手术结果的好坏有关，但目前只有在肾上腺被切除后才能获得这些信息。该项目旨在确定由异常肾上腺细胞产生并释放到患者血液中的蛋白质。如果我们能够确定哪些蛋白质与特定的突变有关，我们就可以为患者提供更好的关于治愈手术可能性的建议。这项工作将与一项临床试验同时进行，在该试验中，接受锁孔手术切除整个肾上腺的患者的结果将与仅接受结节选择性射频消融（RFA）的患者进行比较。这是其他医学分支中的一项既定技术，涉及使用射频波燃烧肿瘤细胞。将对结果进行分析，以评估这些蛋白质的测量是否可以可靠地预测手术或RFA是否可能有益，或者两种治疗是否都不可能导致治愈。在临床试验中嵌入这个项目有可能特别强大，因为它可能使我们在未来能够指导患者接受最有可能使他们受益的治疗。除了上述内容，我将进行实验室实验，旨在进一步了解PA和肾上腺细胞中控制醛固酮产生的方式。最近发现了一种新的导致PA的拼写错误（称为CADM 1突变），但这导致异常醛固酮产生的方式尚未被理解。实验将探索这种突变是否会导致醛固酮产生的自然昼夜波动变得扭曲，这是否与相邻细胞相互交流方式的变化有关，以及神经细胞是否在这一过程中发挥作用。发展我们对醛固酮在细胞水平调节的理解是重要的，因为它可能导致我们确定PA可以用药物治疗的新方法。

Hypertension (high blood pressure) is a common condition which increases an affected individual's risk of serious health complications including kidney failure and stroke. In 5-10% of cases, hypertension is attributable to primary aldosteronism (PA). In this condition, cells in or both adrenal glands (which sit on top of the kidneys at the back of the abdomen) develop mutations ('spelling mistakes' in the DNA) that lead to inappropriately high blood levels of the hormone aldosterone. This causes sodium (salt) retention in the body and increases blood pressure. PA carries a higher risk of heart disease than high blood pressure from other causes and has specific treatment options. It is estimated that currently, due to a number of factors, less than 1% of patients with PA are investigated and treated. In approximately half of patients the abnormal hormone levels come from a discrete benign nodule (tumour) in one adrenal gland; in the other half the problem is more diffuse and affects both glands. Treatment options consist of either surgery or medication which is designed to counter the effects of aldosterone. Guidelines advise that surgery to remove an adrenal gland is the preferred choice of treatment in cases where the excess aldosterone is predominantly arising from one rather than both glands. Identifying such patients involves an invasive procedure which requires specific expertise and outcomes following surgery are variable. While some patients are cured of hypertension, others experience no benefit or are only partially cured. Prof Brown and his team haves extensive experience of researching PA, with the goal of making it easier to diagnose and treat; and of selecting the right patient for the right treatment. Certain mutations seem to be associated with better or worse outcomes from surgery, but at present this information is only available once the adrenal gland has been removed.This project seeks to identify proteins that are made by the abnormal adrenal cells and released into the patient's blood. If we can identify which proteins are associated with particular mutations we could offer patients much better advice about the likelihood of curative surgery. The work will take place alongside a clinical trial in which outcomes of patients undergoing keyhole surgery to remove the whole adrenal will be compared to those undergoing selective radiofrequency ablation (RFA) of just the nodule. This is an established technique in other branches of medicine which involves burning tumour cells using radiofrequency waves. The results will be analysed to assess whether measurement of these proteins can reliably predict whether surgery or RFA is likely to be beneficial or whether neither treatment is likely to be to result in a cure. Embedding this project in the clinical trial has the potential to be particularly powerful as it may enable us in future to direct patients toward treatments most likely to benefit them. Alongside the above, I will undertake laboratory experiments designed to further our understanding of PA and the ways in which aldosterone production is controlled in adrenal cells. A new spelling mistake (called a CADM1 mutation) causing PA has recently been discovered but the ways in which this leads to abnormal aldosterone production have yet to be understood. Experiments will explore whether this mutation causes the natural day-night fluctuations in aldosterone production to become distorted, whether this is relates to changes in the way neighboring cells communicate with each other and whether nerve cells play a part in this process. Developing our understanding of aldosterone regulation at cell level is important as it may lead us to identify new ways in which PA may be treated with medications.