Role of the extracellular calcium-sensing receptor (CAR) in lung development and function

A baby's lungs grow steadily throughout pregnancy until they are almost fully formed by the time it is born. After birth, the mature lungs are completely responsible for obtaining all the oxygen that we need from the air that we breathe. However, the correct functioning of the lungs may be seriously affected if there is a problem with normal lung development in the womb. Such problems might occur if a baby is born too early or if there is a malformation of the chest cavity. In both circumstances the ability of the lungs to take up enough oxygen is reduced. Very recently we have shown that in the womb lungs have a sensor molecule which can detect very small changes in the amounts of certain chemicals within the lung itself or within the blood supply to the lung. This suggests to us that this sensor molecule might control how the lung grows and also that problems with this sensor might lead to disease. To test this suggestion, we will breed mice which do not have this sensing molecule and study how the lungs grow in these animals. Next, we will study how the sensor actually works in the lung and will find out what happens when this sensor is prevented from working using a new set of drugs that we recently been given by a pharmaceutical company. These experiments will give us a greater understanding of how lungs grow, will help us to define how this important sensing molecule works and should lead to the possibility of treating people whose lungs have failed to develop correctly in the womb.

Embryonic lung development is tightly controlled and requires the integration of a variety of growth factors. Although the mechanisms driving lung morphogenesis are intrinsic, extrinsic factors, which are present in utero and that change dramatically at birth (e.g. oxygen and pressure), have profound influence on this developmental programme. Plasma calcium is one such factor which changes at birth but its role in lung development is unknown. In many tissues, extracellular calcium exerts its effects via stimulation of a specific G protein-coupled receptor. This protein is known as the extracellular Calcium-sensing Receptor, CaR. We now have exciting evidence to show that CaR has a narrow window of expression in embryonic mouse lung (E11.5-E16), which coincides with the stage at which branching morphogenesis takes place. Further, we have shown that branching is exquisitely sensitive to changes in extracellular calcium, and that pharmacological agonists of CaR mimic the inhibitory effect of high calcium on branching whilst CaR antagonists partly reverse this inhibition. Based on these data, we hypothesize that extracellular calcium, acting through the CaR, is an important extrinsic factor which modulates the intrinsic lung developmental programme. We will employ three approaches to test this hypothesis. Firstly, comparisons of lung phenotype will be made between CaR wild-type, heterozygous and homozygous mice. Secondly, the effects of specific CaR manipulation in wild-type animals will be probed using pharmacological modulators of CaR function in the lung branching morphogenesis model. Finally, functional consequences of CaR manipulation will be assessed electrophysiologically by measuring transepithelial potential difference in the lung explants from the three cohorts of mice. These experiments will define the role of CaR in lung development and should lead to the possibility of treating diseases characterized by hypoplastic lungs.