A global research team, comprising scientists from DZNE, University Hospital Bonn, the Netherlands, and the US has been awarded a US$ 1.3 million grant by the “Human Frontier Science Program” to analyze brain immune cells and manipulate them via light irradiation. It will involve using gene transcripts (mRNAs) as molecular mediators. From these laboratory studies, the scientists aim to realize recent insights into how these cells change their shape in response to hazards and the role they play in neurodegenerative diseases akin to Alzheimer’s.
The brain houses a special class of immune cells called “microglia” that eliminate toxins, remove cellular debris, and fight pathogens, helping to maintain the brain healthy. “These immune cells move through the tissue, surveying the local environment with little processes. When the microglia sense a danger, they’re activated, which is related to changes of their morphology. First, the size and branching of their projections change and eventually, the microglia tackle a blob-like shape,” said Dr. Dragomir Milovanovic, a biochemist and research group leader at DZNE’s Berlin site. “This transformation is crucial for the immunological function of microglia. Nevertheless, how this dynamic behavior is achieved is unclear. With our studies, we hope to learn more in regards to the mechanisms involved on this. It is understood that in Alzheimer’s microglia change into overactive and that their initially useful effect escalates right into a chronic inflammatory response. Thus, a greater understanding of microglia could assist in devising recent therapies.”
A switch for microglia behavior
For this endeavor, Milovanovic is cooperating with three colleagues, including Prof. Kathrin Leppek from University Hospital Bonn in Germany, in addition to fellow researchers from University of Utrecht within the Netherlands, and from University of California, Berkeley. “We’re an interdisciplinary team, with each member bringing their specific 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 Profession Research Grant” of the Human Frontier Science Program (HFSP), the international collaboration goals to review microglia in mouse brains and to control microglia behavior in cell cultures via photosensitive molecules and laser light. “We intend to develop compounds that influence the production of proteins. Specifically, proteins significant to changes in microglia morphology. The important thing point is that the compounds we are going to synthesize are photoswitchable. Thus, their effect on protein production will be controlled with an appropriate light source. It 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 which might be produced within the cell’s periphery, including its processes. This requires gene transcripts called “mRNAs” in addition to molecular machines that “translate” mRNA molecules into proteins. “It seems, and that is something we wish to analyze intimately, that the mRNAs relevant for morphological changes are packaged along with protein factories into so-called granules. This happens near the cell’s nucleus. From there, these granules that resemble tiny droplets suspended in a unique liquid, are transported to other sites”, Milovanovic explained.
Subsequently, our collaboration goals to discover mRNAs involved within the morphological changes and develop light-sensitive compounds that may attach to mRNAs to manage their transport and protein production at specific places within the cell. For this, we want to discover and characterize microglia mRNAs that we will specifically goal with light-switchable RNA tools. With this revolutionary approach, we wish to contribute to a greater understanding of the biology of microglia and their role in diseases. Our studies may pave the strategy to novel therapies.”
Prof. Kathrin Leppek, an RNA biochemist and research group leader on the Institute of Clinical Chemistry and Clinical Pharmacology of University Hospital Bonn
A competitive selection procedure
The project is ready to run for 3 years. Acquiring the grant was a highly competitive process, because the success rate for applications was only 6.5 percent. “The winners on this 12 months’s HFSP Research Grant Program are remarkable scientists pioneering life science research that needs international collaboration and basic science in frontier subjects – that’s, investigations for which there aren’t any prior studies,” said Pavel Kabat, HFSP Secretary-General. “I used to be thrilled with the proposals we received and sit up for the ground-breaking discoveries that might be revealed.”
Source:
DZNE – German Center for Neurodegenerative Diseases