A multinational study team led by experts from DZNE, University Hospital Bonn, and the Netherlands studied brain immune cells and used laser irradiation to alter them. As molecular mediators, gene transcripts (mRNAs) will be used. Scientists want to learn more about how these cells change their form in response to danger and their function in neurodegenerative illnesses like Alzheimer's through laboratory research.
The brain has a kind of immune cell called "microglia" that eliminates poisons, removes cellular waste, and fights infections, all of which contribute to brain health. "With little processes, these immune cells move through the tissue, surveying the local environment." When microglia detect a threat, they become activated, which causes changes in their morphology. "First, the dimensions and branching of their projections change, and the microglia eventually take on a blob-like shape," explained Dr. Dragomir Milovanovic, a scientist and study group head at DZNE's Berlin facility. "This transformation is required for microglia to function immunologically."
However, it is not obvious how this dynamic behaviour is produced. With this research, we want to understand more about the mechanisms at work. Microglia are known to become hyperactive in Alzheimer's disease, and their initially helpful impact progresses into a chronic inflammatory response. As a result, a greater knowledge of microglia may aid in the development of novel therapeutics."
A Switch for Microglia Behavior
For this endeavour, Milovanovic is cooperating with three colleagues, including Prof. Kathrin Leppek from University Hospital Bonn in Germany, as well as fellow researchers from the University of Utrecht in the Netherlands, and from the University of California, Berkeley. "We are an interdisciplinary team, with each member bringing their expertise to the table. This includes cell biology, RNA and protein biochemistry, synthetic chemistry and other areas," the DZNE scientist explained. Supported by an "Early Career Research Grant" of the Human Frontier Science Program (HFSP), the international collaboration aims to study microglia in mouse brains and to manipulate microglia behaviour in cell cultures by means of photosensitive molecules and laser light. "We intend to develop compounds that influence the production of proteins. Specifically, proteins are significant to changes in microglia morphology. The key point is that the compounds we will synthesize are photoswitchable. Thus, their effect on protein production can be controlled with an appropriate light source. This will allow us to specifically manipulate the morphology of microglia and hence their immunological function with light", Milovanovic noted. He and his colleagues are looking forward to joining forces for this project. The grant will enable them to recruit PhD students or postdocs who will work highly collaboratively.
Targeting Protein Production
Recent studies suggest that the morphological transformation of microglia is regulated by proteins that are produced in the cell's periphery, including its processes. This requires gene transcripts called "mRNAs" as well as molecular machines that "translate" mRNA molecules into proteins. "It seems, and this is something we want to investigate in detail, that the mRNAs relevant for morphological changes are packaged together with protein factories into so-called granules. This happens close to the cell's nucleus. From there, these granules that resemble tiny droplets suspended in a different liquid, are transported to other sites", Milovanovic explained.
"Therefore, our collaboration aims to identify mRNAs involved in the morphological changes and develop light-sensitive compounds that can attach to mRNAs to regulate their transport and protein production at specific places in the cell. For this, we need to identify and characterize microglia mRNAs that we can specifically target with light-switchable RNA tools," said Prof. Kathrin Leppek, an RNA biochemist and research group leader at the Institute of Clinical Chemistry and Clinical Pharmacology of University Hospital Bonn. "With this innovative approach, we want to contribute to a better understanding of the biology of microglia and their role in diseases. Our studies may pave the way to novel therapies."
A Competitive Selection Procedure
The project is set to run for three years. Acquiring the grant was a highly competitive process, as the success rate for applications was only 6.5 per cent. "The winners in this year's HFSP Research Grant Program are remarkable scientists pioneering life science research that needs international collaboration and basic science in frontier subjects - that is, investigations for which there are no prior studies," said Pavel Kabat, HFSP Secretary-General. "I was thrilled with the proposals we received and look forward to the ground-breaking discoveries that will be revealed." (ANI)