Glycobiology of Inflammatory Lung Diseases

Project 1: Treating lung inflammation by targeting Siglecs

Airway inflammation in asthma is typified by eosinophil influx, whereas in COPD neutrophils are prominent. Siglec‐8 is expressed on human eosinophils, mast cells and basophils (allergic inflammatory cells), and Siglec‐9 on neutrophils (and some other leukocytes). Engagement of these Siglecs damps inflammatory cell activation and/or induces their death. The goals of this project are to target Siglec‐8 to treat asthma and Siglec‐9 to treat COPD by diminishing the survival and/or activation state of eosinophils and neutrophils, respectively. Using the tools generated in Project 2, we will probe human eosinophils and neutrophils, and murine models of asthma and COPD (including new Siglec‐8 and Siglec‐9 transgenic mice), to test the hypothesis that glycan‐driven engagement of siglecs has therapeutic potential in inflammatory lung diseases. Link to LIDPEG Website


Project 2: Siglec-targeted nanoparticles for lung and cardiovascular disease

Nanoparticles decorated with siglec ligands can deliver cargo to specific cells expressing that siglec. Nanoparticles decorated with ligands for Siglec‐8 will be used to target eosinophils, Siglec‐9 to target neutrophils, and Siglec‐1 to target macrophages. Nanoparticles targeting leukocytes will be tested for their activity using human cells and murine models of allergic asthma (Siglec‐8) and COPD (Siglec‐9) in collaboration with Project 1. Siglec‐1‐targeted nanoparticles, which engage macrophages, will be tested for diagnosis and treatment of atherosclerotic plaque in a murine model of atherosclerosis. The results will elucidate roles of specific inflammatory cells in disease progression and probe the potential of siglec‐targeted nanoparticles to diagnose and treat lung and cardiovascular diseases. Link to LIDPEG Website


Project 3: Human lung counter-receptors for Siglec-8 and Siglec-9

Native siglec counter‐receptors in the lung engage Siglec‐8 on allergic inflammatory cells and Siglec‐9 on neutrophils, limiting ongoing inflammation. The native glycoprotein or glycolipid molecules responsible for Siglec engagement are unknown. Project 3 will isolate and, in collaboration with Project 4, characterize the human lung counterreceptors for Siglec‐8 and Siglec‐9. Counter‐receptor expression will be characterized on normal and diseased human lung epithelial and endothelial cells, and the enzymes responsible for their biosynthesis will be determined. Discovering human lung counter‐receptors for Siglec‐8 and Siglec‐9 will enhance understanding of the progression of lung inflammatory diseases and may provide improved lead structures for anti‐inflammatory therapeutics. Link to LIDPEG website


Project 4: Regulated expression of siglec counter-receptors

We hypothesize that expression of siglec counter‐receptors is regulated by innate signaling mechanisms that coordinate the expression of these potent anti‐inflammatory glycans. The glycome of human lung tissue and isolated lung cell types will be characterized by mass spectrometry and orthogonal analytic approaches to define the diversity of potential siglec counter‐receptors. In collaboration with Project 3, human lung siglec counter‐receptors will be characterized. Innate regulatory networks appear to control glycan expression. Therefore, dynamic changes in glycan expression will be assessed following cytokine and Toll‐like receptor agonist administration to lung epithelial and endothelial cells. Identifying endogenous counter‐receptors for siglecs and the signaling pathways that regulate their expression may provide new classes of anti‐inflammatory therapeutic development. Link to LIDPEG website


Core D: Inflammatory Animal Models Core

Core D has established mouse models of allergic asthma and COPD, and will generate several new strains of transgenic humanized and knockout mice. Our aim is to study mechanisms in the regulation of siglec ligand synthesis in the lung and to test glycan ligands and mimetics to treat lung inflammation. The Core uses molecular, cellular, immunological, histological and physiological technologies and methods to analyze the effects of siglec-targeted ligands on eosinophilic and neutrophilic mice. Link to LIDPEG website