Glycobiological Modulation of Neuroinflammation: Exploring Innovative Therapeutic Approaches for Neurological Disorders

Jeya Chelliah B.Vsc  Ph.D.

Neuroinflammation, characterized by the activation of glial cells and the release of pro-inflammatory mediators in the central nervous system (CNS), is a hallmark of various neurological disorders, including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. While considerable progress has been made in elucidating the molecular and cellular mechanisms underlying neuroinflammation, novel therapeutic strategies targeting this process remain limited. Here, we propose an innovative approach that integrates principles from glycobiology, immunology, and molecular neuroscience to uncover novel pathways for modulating neuroinflammation and mitigating neuronal damage. Our hypothesis is that glycan-mediated interactions play a pivotal role in regulating the activation and function of microglia, the resident immune cells of the CNS, and thereby modulate neuroinflammatory responses. By targeting specific glycan modifications and glycan-binding proteins expressed on microglia, we aim to manipulate their activation state and inflammatory phenotype, leading to reduced neuroinflammation and improved neuronal survival. This interdisciplinary research proposal represents a paradigm shift in our understanding of neuroinflammatory mechanisms and holds significant promise for the development of innovative therapeutic interventions for neurological disorders.

Neuroinflammation is a complex pathological process involving the activation of microglia and astrocytes, infiltration of peripheral immune cells, and dysregulation of cytokine and chemokine signaling in the CNS. While neuroinflammation serves as an innate immune response to various insults, chronic or dysregulated inflammation can exacerbate neuronal damage and contribute to the progression of neurological disorders. Current therapeutic approaches targeting neuroinflammation often focus on broad immunomodulatory strategies, which may lack specificity and carry potential side effects. Thus, there is an urgent need for novel therapeutic interventions that can selectively modulate neuroinflammatory responses while preserving physiological immune function within the CNS.

Hypothesis: We propose that glycans, complex carbohydrate molecules attached to proteins and lipids, play a crucial role in regulating microglial activation and neuroinflammatory responses in the CNS. Glycans are known to mediate cell-cell interactions, modulate immune cell signaling, and regulate protein function through glycan-binding proteins (lectins) and glycosyltransferases. We hypothesize that specific glycan modifications on microglial surface receptors and extracellular matrix proteins influence their activation state and inflammatory phenotype in response to CNS insults. Furthermore, we propose that targeting these glycan-mediated interactions using small molecules or glycan-based therapeutics can modulate microglial function and attenuate neuroinflammation in neurological disorders.

Approach:

1. Characterization of glycan signatures on activated microglia:
   • Utilize cutting-edge glycomic profiling techniques to identify unique glycan modifications associated with activated microglia in vitro and in vivo.
   • Investigate the dynamic changes in microglial glycosylation patterns during neuroinflammatory responses induced by various stimuli, including lipopolysaccharide (LPS), amyloid-beta peptides, and inflammatory cytokines.
2. Functional analysis of glycan-binding proteins in microglial activation:
   • Screen a library of glycan-binding proteins (lectins) to identify candidates that specifically recognize microglial glycans associated with neuroinflammation.
   • Characterize the binding affinity and functional consequences of lectin engagement on microglial activation, cytokine production, and phagocytic activity.
3. Development of glycan-targeted therapeutics for neuroinflammatory modulation:
   • Design and synthesize glycan-based compounds or glycan mimetics that selectively target microglial glycan receptors involved in neuroinflammation.
   • Evaluate the efficacy and safety of glycan-targeted therapeutics in preclinical models of neurological disorders, assessing their ability to attenuate neuroinflammation, preserve neuronal integrity, and improve cognitive function.

Significance: This interdisciplinary research proposal represents a novel and transformative approach to understanding the role of glycobiology in neuroinflammation and neurodegeneration. By elucidating the glycan-mediated mechanisms underlying microglial activation and inflammatory responses, this research has the potential to uncover new therapeutic targets and strategies for treating a wide range of neurological disorders. Furthermore, the development of glycan-targeted therapeutics could offer a promising avenue for precision medicine approaches tailored to individual patients based on their specific glycomic profiles and disease phenotypes. Overall, this research proposal aims to advance our understanding of neuroinflammatory mechanisms and pave the way for innovative treatments that mitigate neuronal damage and improve patient outcomes in neurological disorders.