Cell-cell recognition occurs when complementary molecules on apposing cell surfaces meet. A receptor on one cell surface binds to its ligand (counter-receptor) on a nearby cell, initiating a cascade of events that regulate cell behaviors ranging from simple adhesion to complex cellular differentiation to cell death. Glycans (glycoproteins, glycolipids, proteoglycans) richly decorate all cell surfaces, and represent the most prominent class of cell surface molecules. Members of this large and varied family are ligands for complementary binding proteins, lectins, on nearby cells.
Lectin-carbohydrate interactions mediate cell-cell interactions throughout the body. The study of cell surface glycans, lectins, and their roles in cell physiology are part of the rapidly expanding field of GLYCOBIOLOGY.
Cell-cell interactions in inflammation
The lectin SIGLEC-8 was discovered on human eosinophils, basophils, and mast cells - the cells that drive allergic inflammation including asthma. Engaging Siglec-8 on the surface of these cells results in apoptosis and inhibition of immune mediator release, inhibiting allergic inflammation. We identified a glycan structure that binds to Siglec-8 and that represents a lead compound for glycan-based asthma therapy, and we are now seeking the endogenous counter-receptors in human lung that control eosinophilic inflammation.
Likewise, the related lectin SIGLEC-9 is expressed on human neutrophils and monocytes. Engaging Siglec-9 results in neutrophil apoptosis. We are seeking the human lung counter-receptors responsible in an effort to design inhibitors of neutrophilic lung inflammation in diseases such as chronic obstructive pulmonary disease (COPD, emphysema).
These efforts are part of our NHLBI-funded "Lung Inflammatory Disease Program of Excellence in Glycoscience" (LIDPEG).
Sialoglycans in the control of nervous system structure and function
Excitatory circuits in the brain are actively and dynamically regulated to ensure appropriate functioning while providing synaptic plasticity that leads to learning and memory. Quantitative and qualitative changes in synaptic expression of AMPA-type glutamate neurotransmitter receptors (AMPARs) play particularly important roles in these processes. Knowledge of the molecular machinery that controls AMPAR trafficking in and out of the postsynaptic membrane provides insights into synaptic plasticity in health and disease. We discovered that gangliosides, major nerve cell surface sialoglycans, control AMPAR trafficking. Human congenital disorders of ganglioside biosynthesis result in deficits in learning and memory and seizure susceptibility, pathology that is phenocopied in mouse genetic models. The discovery that AMPARs and AMPAR trafficking proteins, engage with specific brain gangliosides provides an unanticipated opportunity to understand the roles of gangliosides in regulating excitatory neurotransmission at the cellular, molecular, and whole organism levels.
HIV-associated neurocognitive disorder (HAND)
Great advances in the control of HIV/AIDS have lessened the mortality of this devastating viral infection. Despite these advances, a serious side effect of HIV infection still troubles many patients, HIV-associated neurocognitive disorder (HAND), which can vary in severity from mild alterations in cognition to dementia. The molecular basis for HAND is not well understood, but may involve the persistence of the HIV viral protein Tat and its ability to bind to the NMDA-type of glutamate neurotransmitter receptors. This program aims to probe the molecular basis for this interaction in an effort to provide new avenues for therapies to stop this side effect of HIV infection.
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