Periodic Reporting for period 2 - CALVARIA (Translational aspects of the discovery of skull marrow – meninges connections)
Okres sprawozdawczy: 2022-07-01 do 2023-12-31
Neurodegenerative diseases (NDs), considered the 21st-century epidemic, are characterized by brain inflammation. This project aims to leverage recently discovered skull-meninges connections (SMCs) to address this issue. Through tissue-clearing methods, it has been found that the calvaria bone marrow directly connects to brain meninges, suggesting involvement in various brain pathologies. This accessibility makes it attractive for drug delivery and potential biomarker detection. However, detailed SMC and calvaria characteristics and their correlation with neuropathology are unknown. High-throughput technologies will be used to investigate these aspects in ischemic stroke and dementia models, pursuing diagnostic and therapeutic potential. The main objectives are to: 1) Investigate calvaria's molecular, cellular, and structural aspects in physiological states. 2) Explore therapeutic manipulation of calvaria to mitigate stroke and dementia. 3) Develop diagnostic calvaria imaging for stroke and dementia monitoring.
With neurodegenerative diseases being a significant socio-economic burden, this research could yield innovative diagnostic and therapeutic targets, ultimately impacting public health. The project addresses the structural, cellular, and molecular profiles of the calvaria's connection to brain meninges and its potential to manage neuroinflammation. As a pioneering investigation into the impact of the skull on brain function, the study leverages advanced techniques to explore this new avenue of research.
With neurodegenerative diseases being a significant socio-economic burden, this research could yield innovative diagnostic and therapeutic targets, ultimately impacting public health. The project addresses the structural, cellular, and molecular profiles of the calvaria's connection to brain meninges and its potential to manage neuroinflammation. As a pioneering investigation into the impact of the skull on brain function, the study leverages advanced techniques to explore this new avenue of research.
In our project's initial phase, we have made significant advances, uncovering distinct responses of specific marrow cells within the cranial region to brain injuries. These cells are crucial in orchestrating complex immune responses linked to neuroinflammation. Our research, involving post-mortem tissues from diseased patients with stroke, multiple sclerosis, and Alzheimer's disease animal models, reveals noteworthy parallels between immune cells in the skull marrow and those in the meninges, suggesting collaborative immune functions. Further, our in-depth post-injury transcriptomics and proteomics analysis sheds light on essential proteins influencing immune modulation and broader cellular activities. The study uncovers dynamic responses of skull marrow cells to brain injury, hinting at potential myeloid cell migration from the skull marrow to the brain. Deep learning and innovative 3D imaging techniques have helped us visually capture the physical connections between the skull and the meninges, enhancing our understanding of their interdependence. On an innovative trajectory, our research now extends to SARS-CoV-2 long COVID-19 neurological symptoms, revealing significant spike protein persistence within the skull marrow and meninges of recovered individuals, possibly contributing to the extended neurological effects post-recovery (long COVID).
This project marks a significant advancement in comprehending the intricate calvaria-meninges-brain axis and its implications for neuroinflammation. These findings underscore the significance of the skull's distinct responses in the calvaria-meninges-brain axis, differentiating it from other bones. The discovery of spike protein-induced brain injuries and the persistence of spike protein within the skulls of recovered individuals presents a unique vantage point for decoding neurological effects post-COVID. This project is an exploration of the dynamic relationship between the calvaria, meninges, and brain, shaping the future understanding of neuroinflammation. Notably, our insights position the skull as a potential diagnostic tool for brain conditions, opening avenues for innovative diagnostic and therapeutic approaches with far-reaching implications for improving brain health and well-being in society.