Form follows function: Morphological and molecular diversity of astrocytes in an inflammatory environment

• Applicants: Professor Dr. Tim Clarner; Professor Dr. Markus Kipp
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508026186

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is characterized by myelin loss, peripheral immune cell recruitment into the CNS, axonal damage as well as microglia and astrocyte activation. Recent studies revealed that astrocytes are multi-functional cells in neuronal homeostasis as well as in central nervous system (CNS) disease. Astrocytes display remarkable flexibility and variability of their morphology and biochemical output, participating in both pathogenic and beneficial changes. In many cases, cell morphology and cell function are inseparably intertwined. In MS, activated astrocytes might influence various processes that are critically involved in the formation of inflammatory lesions, such as local glia responses, the breakdown of the Blood Brain Barrier and the recruitment of leukocytes into the CNS. The functional phenotype of activated astrocytes thereby can be either detrimental or protective and is thought to be reflected by morphological changes. On the molecular level, a key player in the astrocyte-mediated regulation of lesion formation might be the small secreted protein Lipocalin 2 (LCN2). We hypothesize that a sub-population of perivascular astrocytes exits in the brain that responds to (autoimmune-) inflammatory processes by the production and secretion of LCN2, thus potentially modulating local inflammatory responses and the entry of (autoimmune) lymphocytes into the brain. In this project we will adopt the neuron tracing and reconstruction software “Neurolucida360” to quantify astrocyte morphology, thus implementing “Glialucida360”. Key morphological parameters, among cell volume, process complexity, or astrocyte polarity will be quantified in control and experimental inflammatory demyelination models. For the very first time, we will analyze the consequence of innate and adaptive immunity encounter for astrocyte morphology and function. To subject astrocytes to different pathological conditions, we will use three distinct injury paradigms which all show CNS demyelination. The very same animal models will be used to analyze the function of LCN2-expressing astrocyte subpopulations for inflammatory lesion development. Besides astrocyte-specific LCN2-/- mice, we will use FAC sorting, flow cytometry, electron microscopy, single cell sequencing and cell culture approaches to reveal how LCN2 regulates astrocyte function.

• DFG Programme: Research Grants