Project description
Exploiting skull-meninges connections to control brain pathologies
As more and more people around the world are living longer, society is facing growing challenges arising from neurodegenerative diseases affecting millions of people. The recent discovery of the skull-meninges connections (SMCs) that can mediate immune cell trafficking into the brain is extremely promising for new diagnostics and treatments. However, the comprehensive cellular and structural features of the SMCs and the skull/calvaria need further research. The EU-funded CALVARIA project will use advanced experimental technologies of tissue clearing, proteomics and single-cell RNA sequencing to investigate possible exploitation of the discovery for easier access from the skull/calvaria bone marrow, enabling better drug delivery into the brain, control of neuroinflammation and easier detection of brain pathologies.
Objective
Neurodegenerative diseases (NDs) are labeled as the epidemic of the 21st century. The inflammation of the brain is a common pathology observed in many NDs. Here I aim to exploit our discovery of skull – meninges connections (SMCs) mediating immune cell trafficking into the brain to ease this healthcare burden. Using tissue clearing methods, we found that the skull (calvaria) bone marrow is directly connected to the brain meninges, a discovery that was also shown by an independent group around the same time. This finding suggests that the calvaria is involved in diverse brain pathologies. Easier accessibility of the calvaria compared to brain parenchyma also makes it an attractive region to target, which would alleviate hurdles of drug delivery into the brain, e.g. to control neuroinflammation. Furthermore, potential biomarkers in the calvaria reflecting pathologies of the brain could be easier and faster to detect. However, the detailed structural and cellular characteristics of the SMCs and the calvaria, and how they correlate and interact with neuropathology remain unknown. Here, we will utilize high-throughput technologies such as tissue clearing, single cell RNAseq, proteomics and unbiased analysis of data using deep learning to close this knowledge gap. We will use ischemic stroke and dementia models that are associated with acute and chronic neuroinflammation, respectively, and study both mouse and human tissues in parallel to validate potential clinical implications.
This project will investigate followings:
Aim 1 | Calvaria in physiological state
Aim 2 | Therapeutic aspect: manipulation of calvaria to control stroke and dementia
Aim 3 | Diagnostic aspect: calvaria imaging to monitor stroke and dementia
Thus, the first in-depth investigation of the calvaria bone in health and disease could deliver novel diagnostic and therapeutic targets to mitigate the increasing burden of neurological diseases.
Fields of science
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesbasic medicineneurologydementia
- medical and health sciencesbasic medicinepathology
- natural sciencescomputer and information sciencesartificial intelligencemachine learningdeep learning
- medical and health sciencesbasic medicineneurologystroke
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
85764 Neuherberg
Germany