Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars

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DESCRIPTION (provided by applicant): Trafficking of leukocytes to skin is directed by adhesive interactions between vascular endothelial selectins and leukocyte selectin ligands. Leukocyte selectin ligand activity is conferred by specialized carbohydrate structures displayed on leukocyte surface proteins. These specialized carbohydrates expressed on distinct subsets of leukocytes impart the capacity of leukocytes to enter skin and are, thus, otherwise referred to as skin-homing receptors. To this end, controlling the migration of skin-homing leukocytes associated with skin disorders, such as atopic dermatitis, allergic dermatitis, psoriasis and cutaneous leukemias, with selectin ligand-modifying sugar mimetics represents a potentially promising therapeutic strategy. The effects of over-the-counter glucosamine formulations have been purported to relieve arthritic conditions and are supportive of this notion. Preliminary data from our laboratory show that a simple fluorinated glucosamine analog (or fluoro-glucosamine) of naturally-occurring glucosamine modulates carbohydrate structures required for leukocyte selectin ligand activity, causing attenuated cutaneous inflammatory responses. We hypothesize that this fluoro-glucosamine analog can be utilized as a model of Complementary and Alternative Medicinal (CAM) agents, such as glucosamine, to study how and which glycans on effector leukocytes are sensitive to glyco-metabolic inhibition. The objectives of studies in this application are 1.) To define the mechanism of fluoro-glucosamine action on leukocyte selectin ligand and other adhesion molecule expression and 2.) To investigate the in vivo efficacy and specificity of fluoro-glucosamine treatment in mouse models of inflammation. We aim to improve our understanding of how fluoro-glucosamine inhibits dermatotropic activity of effector leukocytes and to determine whether fluoro-sugars affect leukocyte adhesion molecule function involved in other non-skin migration patterns. Numerous biochemical approaches using fresh and cultured leukocytes will be employed to study how fluoro-glucosamines modify leukocyte glycan expression and function. Fluoro-glucosamine efficacy and specificity will be analyzed on effector skin- and non-skin-homing leukocyte subsets using well-defined models of inflammation. The overall goal of this preclinical investigation is to show how fluoro-glucosamines behave as immunomodulators of cutaneous inflammation, providing insight into potential CAM glucosamine efficacy on leukocyte homing receptors. PUBLIC HEALTH RELEVANCE. Mechanistic Analysis of the Anti-inflammatory Activity of Fluorosugars Project Narrative Our laboratory has recently shown that fluorinated sugar analogs of glucosamine elicit anti- inflammatory activity in models of dermatitis. The overall objective of this project is to understand how fluoro-glucosamine inhibits the trafficking of leukocytes to inflamed skin. Our preclinical investigation will demonstrate the utility of fluoro-glucosamines as immunomodulators of cutaneous inflammation and, potentially, help model the effects by complementary and alternative medicines, such as glucosamine.