Deep exploration of the brain hypoxia-EPO circle as a prerequisite for novel therapies in neurodegenerative diseases

• Applicant: Vikas Bansal, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; General Genetics and Functional Genome Biology ; Bioinformatics and Theoretical Biology ; Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513977564

Objectives: Our overall goal is to investigate the EPO-response of four major brain cell types using cell-type specific driver lines: neurons (Nex-Cre), oligodendrocytes (Plp-Cre), astrocytes (Aldh1l1-Cre) and microglia (Cx3cr1-Cre). Based on the previous work by us and others, we hypothesize that EPO, functional and inspiratory hypoxia induce partially overlapping molecular changes in selected cell types. Moreover, some transcriptional and epigenetic responses are expected to be cell-type specific due to the unique response of each cell type to EPO-administration/induction. Transcriptomic and epigenetic changes underlie the cellular adaptation to EPO exposure; therefore, analysis of these transcriptomic and epigenetic changes provides mechanistic insights into how processes of brain plasticity lead to cognitive improvement in response to EPO/CRW/inspiratory hypoxia. To achieve our goal, we attempt to perform extensive characterization of transcriptomic and epigenetic readouts from selected cell types in the mouse brain after mice were exposed to the selected EPO-administration/induction paradigms. This will not only allow a standardized comparison of these paradigms, but also enable a comparison of general versus cell-type specific responses on various molecular levels, i.e. nascent RNA, translating RNA, miRNA and chromatin accessibility. In addition, we will use snRNA-seq to complement the findings of Tagger data and to further dissect the molecular changes in sub cell-types with an increased resolution. These data will provide a comprehensive mechanistic insight into EPO effects in the brain/hippocampus and lay ground for studies towards exploitation of the therapeutic potential of EPO administration, functional hypoxia and inspiratory hypoxia as beneficial and potentially negative effects of each paradigm can be evaluated. Aims: We will employ four Cre-driver lines (Nex-Cre for neurons, Plp-Cre for oligodendrocytes, Aldh1l1-Cre for astrocytes & Cx3cr1-Cre for microglia) to investigate cell-type specific responses to EPO administration, CRW and inspiratory hypoxia. These different EPO-induction methods will be compared with regard to the elicited molecular and cellular changes. Using the Tagger mouse, we will investigate and compare four different molecular readouts (nascent and translating RNA, miRNA, open chromatin) per cell type. Using snRNA-seq, we aim to validate transcriptomic changes found in Tagger data at single-nuclei resolution. The molecular changes will be investigated to find associated signaling pathways involved in neuroplasticity, cellular differentiation, inflammation and cognitive improvements, and also that trigger potentially negative/unwanted cellular changes such as enhanced apoptosis or phagocytosis, generation of reactive oxygen species and cellular stress.

• DFG Programme: Research Grants
• International Connection: Sweden
• Co-Investigators: Professorin Dr. Hannelore Maria Ehrenreich; Professor Peter Heutink, Ph.D.
• Cooperation Partner: Walker Jackson, Ph.D.