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

细胞粘附分子 1 体细胞肾上腺突变对醛固酮生理和病理产生的体内和离体教训

• 批准号: MR/X018970/1
• 金额: $ 40.45万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018970%2F1
• 关键词: vivo; ex; lessons; somatic; adrenal

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.

高血压（高血压）是一种常见状况，可增加受影响的人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，高血压归因于原发性醛固酮（PA）。在这种情况下，肾上腺中或两个细胞（位于腹部后部的肾脏顶部）会出现突变（DNA中的“拼写错误”），导致激素醛固酮的血液水平不适当。这会导致体内钠（盐）保留并增加血压。 PA比其他原因的高血压具有更高的心脏病风险，并且具有特定的治疗选择。据估计，目前，由于许多因素，研究和治疗不到1％的PA患者。在大约一半的患者中，异常激素水平来自一个肾上腺中的离散良性结节（肿瘤）。在另一半中，问题更加分散，并且会影响两个腺体。治疗选择包括手术或药物，旨在应对醛固酮的作用。指南建议，在多余的醛固酮主要由一个而不是两种腺体引起的情况下，去除肾上腺的手术是治疗的首选。确定此类患者涉及一种侵入性手术，该程序需要特定的专业知识和手术后的结果是可变的。虽然有些患者可以治愈高血压，但另一些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方面具有丰富的经验，目的是使诊断和治疗更容易；并选择合适的患者进行正确的治疗。某些突变似乎与手术的更好或更差有关，但是目前只有在去除肾上腺后才能获得此信息。该项目试图鉴定由异常肾上腺细胞产生的蛋白质并释放到患者血液中。如果我们可以确定哪些蛋白质与特定突变有关，则可以为患者提供有关治疗手术可能性的更好建议。这项工作将与一项临床试验一起进行，在临床试验中，接受钥匙孔手术以去除整个肾上腺的患者的结果将与仅在结节的选择性射频消融（RFA）进行比较。这是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还是RFA是否可能是有益的，或者是否没有治疗可能导致治愈。将该项目嵌入临床试验中有可能变得特别强大，因为它可能使我们将来能够将患者带入最有可能受益的治疗。在上述情况下，我将进行实验室实验，旨在进一步了解PA及其在肾上腺细胞中控制醛固酮产生的方式。最近发现了一个新的拼写错误（称为CADM1突变）引起PA，但是导致异常产量产生异常的方式尚未了解。实验将探索这种突变是否导致醛固酮产生的自然昼夜波动会扭曲，这是否与邻近细胞相互通信的方式变化以及神经细胞在此过程中是否起作用。在细胞水平上发展我们对醛固酮调节的理解很重要，因为它可能导致我们确定可以用药物治疗PA的新方法。