Translational aspects of the discovery of skull marrow – meninges connections

ongoing

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.