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Researchers at MHH and LUH are looking for a way to prevent premature closure of the cranial sutures in newborns.
The skull of newborns is not solid, as it is in adults, but flexible. This is important because it must deform during birth in order to fit through the narrow birth canal. The brain also needs a lot of space in the first year of life because it grows extremely quickly. The five plates of the skull gradually grow together, and the last cranial suture does not close completely until adulthood. In some children, however, the cranial sutures ossify too early, sometimes even before birth. This condition, called craniosynostosis, occurs in about one in 2,500 births and leads to a characteristic deformation of the skull.
To date, there is no causal drug treatment that can prevent or stop this condition. Affected children often require surgery to ensure further expansion of the skull. The specific molecular processes responsible for craniosynostosis are still unclear. Mutations in the IL11RA gene, which contains the information for the interleukin-11 receptor (IL-11R), play a role in the malformation. This is the docking site for the messenger substance interleukin-11, which plays an important role in bone metabolism. Prof. Dr Christoph Garbers, head of the Institute of Clinical Biochemistry at Hannover Medical School (MHH), wants to find an approach to interrupt the molecular malfunction and prevent premature closure of the cranial sutures. The project, in cooperation with Leibniz University Hannover (LUH), is being supported with around £1.5 million over three years as part of the ‘Innovative Diagnostics and Therapy Approaches for Combating Rare Diseases’ call for proposals from the zukunft.niederachsen funding programme.
Signal transmission of messenger substance interleukin-11 disrupted
Professor Garbers has been researching the various signalling pathways controlled by interleukin-11 for many years. ‘Our work to date has shown that changes in the IL11RA gene cause the receptor to remain inside the cell and prevent it from being activated by its messenger substance outside the cell,’ explains the biochemist. Because IL-11R is missing from the cell surface, interleukin-11 cannot dock and the signal transmission for the command ‘keep the cranial suture open’ does not take place. Responsible for this are the so-called chaperone proteins in the endoplasmic reticulum (ER), the cell's quality assurance system. Like biochemical ‘chaperones,’ the chaperones check whether proteins that are to be transported out of the cell are correctly folded. If they do not have the correct three-dimensional structure due to gene mutations, further transport is blocked and the protein is retained in the ER.
Removing functional variants from the cell
This control is useful because misfolded proteins usually do not function anyway and, in the worst case, can have harmful effects on the organism. However, Professor Garbers and his team recently discovered that some mutated variants of IL-11R can bind to interleukin-11 after all. ‘In this case, it is therefore bad that they are not transported to the cell surface,’ notes the biochemist. In order to expel these functional variants from the cell, Professor Garbers and his team want to outsmart the ‘chaperones’ of ER quality control. In a first step, the researchers therefore want to characterise all variants in detail and find out which of them are functional despite incorrect folding.
In a second step, they are searching the large group of chaperones for those that are responsible for IL-11R. They have already identified two possible candidates. ‘We will use mass spectrometry to find other proteins in the ER that bind to the IL-11 receptor,’ says Professor Garbers. In a third step, they will finally look for a way to break the bond between the chaperones and the still functional IL-11R variants so that the receptors can leave the cell. Various active substances, such as siRNAs and small molecules, will help to prevent the chaperones from binding and release the IL-11R variants from the ER in order to restore IL-11 signal transduction.
New mini test model of a cranial suture
Further investigation of the potential drug candidates is being carried out at LUH. There, a team led by Prof. Dr Dominik Egger, head of the Biofabrication for Drug Testing department at the Institute of Cell Biology and Biophysics, is testing the efficacy of the previously identified active substances. Until now, there has been a lack of suitable laboratory test models based on human cells. This is now set to change. ‘We are building a three-dimensional, miniaturised model of a cranial suture from specially modified stem cells and biomaterials,’ says Professor Egger, who is co-applicant for the project. The model will be slightly smaller than one cubic centimetre and will be developed on a hydrogel basis. The researchers want to test potential active substances on both healthy and disease-altered stem cells that carry the genetic defect.
‘This project may create the first causal treatment option for craniosynostosis,’ emphasises Professor Garbers. And perhaps proven methods can be used in the process. Pharmacologically active substances that act on misfolded proteins are already being used to treat other diseases such as cystic fibrosis. ‘We therefore also want to investigate whether the drugs developed for this purpose also work in craniosynostosis,’ explains Professor Garbers. ‘In that case, the path to clinical application would be significantly shorter,’ says the licensed pharmacist. However, there is still a lot of research work to be done before that happens.
SERVICE:
Further information is available from Prof. Dr Christoph Garbers, garbers.christoph@mh-hannover.de.
Prof. Dr Christoph Garbers is looking for a way to prevent premature closure of the cranial sutures. ...
Copyright: Karin Kaiser/MHH
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Prof. Dr Christoph Garbers is looking for a way to prevent premature closure of the cranial sutures. ...
Copyright: Karin Kaiser/MHH
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