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

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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.