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Investigating the mechanism of adrenal insufficiency in individuals with porphyria

研究卟啉症患者肾上腺功能不全的机制

基本信息

批准号：
MR/X006492/1
负责人：
Ahmed Al-Salihi
金额：
$ 42.28万
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%2FX006492%2F1
关键词：
Investigating mechanism adrenal insufficiency individuals

项目摘要

Haem is a chemical compound most commonly recognised as a component critical to the production of haemoglobin, which is necessary to bind oxygen in the bloodstream. Haem production involves eight enzymes and a deficiency in any one of these enzymes leads to accumulation of chemicals in the body causing a clinically significant group of disorders known as porphyrias.They are classified into two types: the first type known as acute, mainly affects the nervous system, and patients present with severe abdominal pain, nausea, constipation, confusion and seizures, which may be life threatening; the second type known as cutaneous porphyria, causes skin fragility and blisters. Acute attacks can be triggered by many conditions, such as surgery and infections, with symptoms being similar to those seen with adrenal failure, where important steroid hormones such as cortisol are not produced.As well as being the main component of haemoglobin, haem is also essential for the production of enzymes that take part in the production of steroid hormones. Steroid hormones are crucial for the maintenance and normal functioning of the human body, in addition to representing the core element in its fight or flight response to both external and internal stressors. This process takes place in both the adrenal glands (small glands located on top of the kidneys), and the gonads.Failure of the pathway that leads to production of these hormones due to whatever cause result in a condition known as adrenal insufficiency, which if left untreated could be fatal, particularly, during what is known as adrenal crisis, which is basically a disease state in which the steroid producing capacity of the adrenals does not meet the demand.Recently, we have discovered severe defects in haem synthesis enzymes giving rise to adrenal insufficiency as well as porphyria even when the patients are not stressed. We therefore think there may be a spectrum of disease in porphyria and many patients may have unrecognised, life-threatening adrenal disease, which could be amenable to treatment with simple hormone replacement regimes.By utilising cell and mouse models, we will investigate the role of the haem enzymes in normal adrenal gland steroid production and in the diseased state. This will be achieved by creating mutations in adrenal cell lines grown in cell cultures to produce cells that lack the enzymes, we will then measure the levels of different chemicals including cortisol and haem. This will lead to understanding the exact mechanism of these conditions and the level of residual enzyme activity required to maintain normal function. We hope to go on and measure steroids in patients with different porphyrias to see to what degree these changes are translated in humans. This will allow us to suggest appropriate interventions in terms of adding steroids to their treatment which would be helpful long-term or, alternatively, for those suffering acute crises.

血红素是一种化合物，最常被认为是血红蛋白生成的关键成分，而血红蛋白是结合血液中的氧气所必需的。血红素的产生涉及八种酶，其中任何一种酶的缺乏都会导致化学物质在体内积聚，导致一组临床上显着的疾病，称为卟啉症。它们分为两种类型：第一种类型为急性，主要影响神经系统，患者出现严重腹痛、恶心、便秘、意识模糊和癫痫发作，可能危及生命；第二种类型为急性，主要影响神经系统。第二种称为皮肤卟啉症，会导致皮肤脆弱和水泡。急性发作可由多种情况引发，例如手术和感染，其症状与肾上腺衰竭相似，肾上腺衰竭时无法产生重要的类固醇激素，如皮质醇。血红素除了是血红蛋白的主要成分外，对于产生参与类固醇激素产生的酶也是必不可少的。类固醇激素对于人体的维持和正常功能至关重要，也是人体对外部和内部压力源的战斗或逃跑反应的核心要素。这个过程发生在肾上腺（位于肾脏顶部的小腺体）和性腺中。无论何种原因，导致生成这些激素的途径失败，都会导致肾上腺功能不全，如果不及时治疗，可能会致命，特别是在所谓的肾上腺危象期间，这基本上是一种疾病状态，其中肾上腺的类固醇生成能力无法满足最近，我们发现血红素合成酶存在严重缺陷，即使患者没有压力，也会导致肾上腺功能不全以及卟啉症。因此，我们认为卟啉症可能存在一系列疾病，许多患者可能患有未被识别的危及生命的肾上腺疾病，这些疾病可以通过简单的激素替代方案进行治疗。通过利用细胞和小鼠模型，我们将研究血红素酶在正常肾上腺类固醇产生和患病状态中的作用。这将通过在细胞培养物中生长的肾上腺细胞系中产生突变来实现，以产生缺乏酶的细胞，然后我们将测量包括皮质醇和血红素在内的不同化学物质的水平。这将有助于了解这些条件的确切机制以及维持正常功能所需的残留酶活性水平。我们希望继续测量患有不同卟啉症的患者的类固醇，看看这些变化在人类身上的转化程度如何。这将使我们能够建议适当的干预措施，在治疗中添加类固醇，这对长期或对那些遭受急性危机的人有帮助。