Abstract
Multiple sclerosis (MS) poses a significant burden on individuals and healthcare systems globally, characterized by chronic inflammation, demyelination, and neurodegeneration within the central nervous system (CNS). Despite extensive research, the exact etiology of MS remains elusive, necessitating innovative approaches to decipher its complex pathogenesis and develop effective treatments. This project proposal aims to elucidate the role of ischemic injury in autoimmunity, with a specific focus on the impact of hypoxia on the blood-brain barrier (BBB) and brain endothelial cells.
The current state-of-the-art in MS research underscores its multifaceted nature, affecting approximately 2.8 million individuals worldwide. While the autoimmune nature of MS is well-established, emerging evidence suggests vascular dysfunction as a contributing factor, leading to hypoxic conditions within the CNS microenvironment. Ischemic injury, resulting from impaired blood flow and oxygen deprivation, has been implicated in triggering inflammatory responses and disrupting immune tolerance mechanisms. Moreover, hypoxia exacerbates neuroinflammation and compromises BBB integrity, amplifying the autoimmune response in MS.
In this context, our scientific objectives are twofold. Firstly, we aim to investigate the role of vascular endothelial dysfunction in MS pathogenesis through dynamic vessel analysis of the retinal microvasculature in MS patients, providing novel insights into vascular abnormalities and their association with neuronal pathology. Secondly, we seek to elucidate the effect of hypoxia-mediated oxidative stress on the BBB using advanced in vitro models incorporating brain microvascular endothelial cells, pericytes, and astrocytes. Additionally, we will explore the regenerative potential of tolerance-inducing dendritic cells (tolDCs) in alleviating hypoxia-induced damage to the BBB.
Overall, this project endeavors to deepen our understanding of the interplay between ischemic injury, hypoxia, and autoimmunity in MS pathogenesis, offering new avenues for therapeutic intervention and personalized management strategies. By unraveling the complexities underlying MS pathology, we aim to pave the way for innovative treatments that alleviate disease burden and improve the quality of life for individuals living with MS.
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