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

高血压是一种常见的疾病，它会增加患者发生严重健康并发症的风险，包括肾衰竭和中风。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（位于腹部后部的肾脏顶部）的细胞或两个肾上腺细胞发生突变（DNA中的“拼写错误”），导致血液中激素醛固酮的水平过高。这会导致钠（盐）滞留在体内并升高血压。与其他原因引起的高血压相比，PA患心脏病的风险更高，并且有特定的治疗选择。据估计，目前由于多种因素，只有不到1%的PA患者接受了调查和治疗。在大约一半的患者中，异常激素水平来自于一个肾上腺的离散良性结节（肿瘤）；另一半的问题更分散，影响两个腺体。治疗选择包括手术或药物，旨在抵消醛固酮的影响。指南建议，在醛固酮过量主要由一个而不是两个腺体引起的情况下，手术切除肾上腺是首选的治疗方法。识别这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。虽然有些患者的高血压被治愈，但其他人没有任何好处或只是部分治愈。布朗教授和他的团队在研究前列腺癌方面拥有丰富的经验，目标是使其更容易诊断和治疗；选择合适的病人进行合适的治疗。某些突变似乎与手术结果的好坏有关，但目前这一信息只有在肾上腺被切除后才能获得。该项目旨在识别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建议，让他们知道治疗性手术的可能性。这项工作将与一项临床试验同时进行，在该试验中，接受锁眼手术切除整个肾上腺的患者的结果将与接受选择性射频消融术（RFA）切除结节的患者进行比较。这是一种在其他医学分支中建立的技术，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可能导致治愈。在临床试验中嵌入这个项目具有特别强大的潜力，因为它可以使我们在未来指导患者进行最有可能对他们有益的治疗。除此之外，我将进行实验室实验，旨在进一步了解肾上腺素和醛固酮在肾上腺细胞中产生的控制方式。最近发现了一种新的拼写错误（称为CADM1突变）导致PA，但其导致醛固酮产生异常的方式尚不清楚。实验将探讨这种突变是否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。发展我们对细胞水平上醛固酮调节的理解是很重要的，因为它可能会引导我们找到用药物治疗PA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.