Researchers from MHH and LUH are investigating how misdirected cell control triggers the closure of the cranial sutures.
Prof. Dr. Christoph Garbers is searching for a way to prevent the premature closure of the cranial sutures. Copyright: Karin Kaiser/MHH
The skull of newborns is not rigid, as it is in adults, but flexible. This is important because it must deform during birth to fit through the narrow birth canal. The brain also needs a lot of space during the first year of life because it grows extremely rapidly. The five plates of the skull therefore 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, known as 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 could prevent or halt this condition. Affected children often require surgery to ensure further expansion of the skull. The specific molecular processes responsible for craniosynostosis remain unclear. Mutations in the IL11RA gene, which contains the genetic code for the interleukin-11 receptor (IL-11R), play a role in this malformation. This receptor serves as a binding site for the signaling molecule interleukin-11, which plays a key role in bone metabolism. Prof. Dr. Christoph Garbers, Director of the Institute of Clinical Biochemistry at Hannover Medical School (MHH), aims to find an approach to interrupt the molecular malfunction and prevent the premature closure of the cranial sutures. The project, in cooperation with Leibniz University Hannover (LUH), is being supported with approximately 1.5 million euros over three years as part of the call for proposals “Innovative Diagnostics and Therapeutic Approaches to Combat Rare Diseases” from the zukunft.niederachsen funding program.
Signal transmission of the messenger substance interleukin-11 disrupted
Professor Garbers has been researching the various signaling pathways controlled by interleukin-11 for years. “Our previous work has shown that changes in the IL11RA gene cause the receptor to remain inside the cell and prevent it from being activated by its signaling molecule outside the cell,” explains the biochemist. Because IL-11R is absent from the cell surface, interleukin-11 cannot bind, and the signal transmission for the command “keep the cranial suture open” does not occur. Responsible for this are the so-called chaperone proteins in the endoplasmic reticulum (ER), the cell’s quality control system. Like biochemical “chaperones,” these proteins check whether proteins intended for transport out of the cell are correctly folded. If, due to gene mutations, they lack the correct three-dimensional structure, further transport is blocked and the protein is retained in the ER.
Shipping functional variants out of the cell
This control makes sense 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 mutation-derived variants of the IL-11R can indeed bind to interleukin-11. “In this case, it is therefore a problem that they are not transported to the cell surface,” the biochemist notes. To release these functional variants from the cell, Professor Garbers and his team aim to outsmart the “chaperones” of ER quality control. As a first step, the researchers therefore intend to precisely characterize all variants and determine which of them are functional despite incorrect folding.
In a second step, they will search the large group of chaperones for those responsible for the 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 the 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, are expected to help in this process by preventing the binding of the chaperones and releasing the IL-11R variants from the ER to restore IL-11 signaling.
New mini-test model of a cranial suture
Further investigation of the potential drug candidates is taking place at LUH. There, a team led by Prof. Dr. Dominik Egger, head of the Biofabrication Department for Drug Testing at the Institute of Cell Biology and Biophysics, is testing the efficacy of the previously identified compounds. Until now, suitable laboratory test models based on human cells have been lacking. This is set to change. “We are building a three-dimensional, miniaturized model of a cranial suture using specially modified stem cells and biomaterials,” says Professor Egger, who is a co-applicant for the project. The model is intended to be slightly smaller than one cubic centimeter and will be developed using a hydrogel-based approach. The researchers plan to test potential active compounds on both healthy stem cells and disease-altered stem cells that carry the genetic defect.
“This project may create the first causal treatment option for craniosynostosis,” emphasizes Professor Garbers. And perhaps it will draw on proven methods. Pharmacologically active substances that target misfolded proteins are already being used for other diseases, such as cystic fibrosis. “We therefore also want to investigate whether the drugs developed for these conditions also work for craniosynostosis,” explains Professor Garbers. “In that case, the path to clinical application would be significantly shorter,” notes the licensed pharmacist. However, there is still a great deal of research work to be done before that happens.
Text: Kirsten Pötzke