Aldosterone regulation in aldosterone-producing cell clusters and its impact on medical management of primary aldosteronism

醛固酮生成细胞簇中的醛固酮调节及其对原发性醛固酮增多症医疗管理的影响

• 批准号: MR/S006869/1
• 负责人: Emily Goodchild
• 金额: $ 37.46万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS006869%2F1
• 关键词: Aldosterone; regulation; aldosterone; producing; cell

Looking for clues to curing a very common cause of high blood pressureA quarter of the world's adult population has high blood pressure, or hypertension. One in ten of those people have an hormonal cause; an excess of the hormone which causes blood pressure to increase. This hormone is called aldosterone and the condition in which people have an excess of it is called primary aldosteronism (PA). There are many root causes of PA, but most cases are caused by one of two problems: 1- a nodule in the adrenal gland which releases excess aldosterone, an 'aldosterone producing adenoma' (APA) and 2- general enlargement of both adrenal glands; 'bilateral adrenal hyperplasia'. Currently, the patient journey to curing PA is long and difficult; it starts with a GP recognising the signs of PA and doing specialist blood tests to look for it. If the blood tests indicate the excess levels of aldosterone, the patient must then have further specialist tests to confirm it, and then go through a process of changing their blood pressure medications, then have a specialist, invasive blood sampling procedure; adrenal vein sampling (AVS). During the AVS, a specialist doctor samples blood from veins which drain each of the adrenal glands, using X-ray guidance. The purpose is to determine whether the source of the hormone excess is from only one adrenal, since in such cases, the patient is offered surgery to remove the culprit adrenal gland. However, interpretation of the results is not straightforward and frequently high levels of aldosterone are present on both sides, even if the amount of aldosterone coming from one gland is higher than the other. We think this may be why, sadly only 50% of patients who get as far as having their adrenal gland removed are cured. Recently there has been a rush of research into PA because evidence has shown it is much more common than we previously thought and new markers, which aid the investigation of PA, have been discovered. These markers have shown that there are clusters of cells which produce excess aldosterone, called aldosterone producing cell clusters (APCCs), which are too small to see on scans. APCCs have been found in a third of "normal" adrenal glands, and increase in frequency with age. They release aldosterone of their own accord and do not respond to the usual messages in the body to stop. We believe that APCCs are the beginnings of APAs. We also believe that they contribute to the ongoing problem of hypertension in the patients who are not cured after their APA is removed, rather than general enlargement of the glands. By doing laboratory experiments, this project aims to find out the details of APCCs, for example - what is involved in their release of aldosterone- what can be done to stop them producing aldosterone- if there is a way to stop them producing aldosterone, or killing them off altogetherWe believe that some molecules might have an impact on the function of APCCs. The molecules have been identified by examination of DNA and immune staining of APCC cells and an example is DPP4, which is the target of a common class of diabetes medications. I will be looking for effects of some of these molecules on cells in petri dishes and on slices of adrenal glands from humans who have had them removed to treat their PA. I will also be looking for these molecules, and other markers such as DNA, in the blood taken during AVS, to see whether they provide any clues to predict which patients would benefit, or not, from surgery. This research is important because it will bring us closer to finding a medical treatment for PA and will help to avoid many patients having unhelpful surgery. It will be carried out primarily by me, a clinical research fellow, supervised and supported by my research team at the Queen Mary University of London's William Harvey Research Institute, which is led by world-leading expert in endocrine hypertension, Professor M Br

寻找治愈高血压一个非常常见的原因的线索世界上四分之一的成年人患有高血压，或高血压。其中十分之一的人有激素的原因;过量的激素会导致血压升高。这种激素被称为醛固酮，人们过量的情况被称为原发性醛固酮增多症（PA）。PA的根本原因有很多，但大多数情况下是由两个问题之一引起的：1-肾上腺中的结节，释放过量的醛固酮，“醛固酮产生腺瘤”（阿帕）和2-双侧肾上腺的一般增大;“双侧肾上腺增生”。目前，患者治疗PA的过程是漫长而困难的;它始于GP识别PA的迹象并进行专业血液检查以寻找它。如果血液检查显示醛固酮水平过高，患者必须进行进一步的专业检查以确认它，然后经历改变血压药物的过程，然后进行专业的侵入性血液采样程序;肾上腺静脉取样（AVS）。在AVS期间，专科医生使用X射线引导从引流每个肾上腺的静脉中抽取血液。其目的是确定激素过量的来源是否仅来自一个肾上腺，因为在这种情况下，患者会接受手术切除罪魁祸首肾上腺。然而，对结果的解释并不简单，即使来自一个腺体的醛固酮含量高于另一个腺体，两侧也经常存在高水平的醛固酮。我们认为这可能是为什么，可悲的是，只有50%的患者谁得到尽可能有他们的肾上腺切除治愈。最近有一个对PA的研究热潮，因为有证据表明它比我们以前认为的要普遍得多，并且发现了有助于PA研究的新标记。这些标志物表明，有一群细胞产生过量的醛固酮，称为醛固酮产生细胞群（APCC），它们太小了，无法在扫描中看到。在三分之一的“正常”肾上腺中发现了APCCs，并且随着年龄的增长而增加。他们释放醛固酮自己的雅阁和不响应通常的信息在体内停止。我们认为，APCCs是APA的开端。我们还认为，他们有助于持续的问题，高血压的患者谁没有治愈后，他们的阿帕被删除，而不是一般的腺体扩大。通过实验室实验，该项目旨在了解APCC的详细信息，例如-什么参与了它们释放醛固酮-可以采取什么措施来阻止它们产生醛固酮-是否有办法阻止它们产生醛固酮，或者杀死它们。我们相信一些分子可能会对APCC的功能产生影响。这些分子已经通过检查APCC细胞的DNA和免疫染色来鉴定，一个例子是DPP 4，它是一类常见的糖尿病药物的靶点。我将寻找这些分子对培养皿中的细胞和肾上腺切片的影响，这些肾上腺切片是为了治疗PA而切除的。我还将在AVS期间采集的血液中寻找这些分子和其他标记物（如DNA），看看它们是否提供任何线索来预测哪些患者将从手术中受益或不受益。这项研究很重要，因为它将使我们更接近于找到PA的医学治疗方法，并将有助于避免许多患者进行无益的手术。它将主要由我，一个临床研究员，监督和支持我的研究小组在玛丽女王大学的伦敦的威廉哈维研究所，这是由世界领先的内分泌高血压专家，教授M Br

项目成果

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

• DOI: 10.1038/s41588-021-00906-y
• 发表时间: 2021-09
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Zhou, Junhua;Azizan, Elena A. B.;Cabrera, Claudia P.;Fernandes-Rosa, Fabio L.;Boulkroun, Sheerazed;Argentesi, Giulia;Cottrell, Emily;Amar, Laurence;Wu, Xilin;O'Toole, Sam;Goodchild, Emily;Marker, Alison;Senanayake, Russell;Garg, Sumedha;Akerstrom, Tobias;Backman, Samuel;Jordan, Suzanne;Polubothu, Satyamaanasa;Berney, Daniel M.;Gluck, Anna;Lines, Kate E.;Thakker, Rajesh V.;Tuthill, Antoinette;Joyce, Caroline;Kaski, Juan Pablo;Karet Frankl, Fiona E.;Metherell, Lou A.;Teo, Ada E. D.;Gurnell, Mark;Parvanta, Laila;Drake, William M.;Wozniak, Eva;Klinzing, David;Kuan, Jyn Ling;Tiang, Zenia;Gomez Sanchez, Celso E.;Hellman, Per;Foo, Roger S. Y.;Mein, Charles A.;Kinsler, Veronica A.;Bjorklund, Peyman;Storr, Helen L.;Zennaro, Maria-Christina;Brown, Morris J.
• 通讯作者: Brown, Morris J.