Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars

描述（由申请人提供）：白细胞向皮肤的运输由血管内皮选择素和白细胞选择素配体之间的粘附相互作用指导。白细胞选择素配体活性是由白细胞表面蛋白质上显示的特殊碳水化合物结构赋予的。这些在白细胞的不同亚群上表达的特殊碳水化合物赋予白细胞进入皮肤的能力，因此也被称为皮肤归巢受体。为此，用选择素配体修饰的糖模拟物控制与皮肤疾病（例如特应性皮炎、过敏性皮炎、银屑病和皮肤白血病）相关的皮肤归巢白细胞的迁移代表了潜在的有希望的治疗策略。非处方葡萄糖胺制剂的作用据称可缓解关节炎病症，并支持这一观点。我们实验室的初步数据表明，天然存在的葡萄糖胺的简单氟化葡萄糖胺类似物（或氟代葡萄糖胺）调节白细胞选择素配体活性所需的碳水化合物结构，导致皮肤炎症反应减弱。我们假设，这种氟-葡糖胺类似物可用作补充和替代药物（CAM）的模型，如葡糖胺，以研究效应白细胞上的聚糖如何以及哪些对糖代谢抑制敏感。本申请研究的目的是1）。明确氟代氨基葡萄糖对白细胞选择素配体和其他粘附分子表达的作用机制;研究氟代葡萄糖胺治疗小鼠炎症模型的体内有效性和特异性。我们的目的是提高我们的理解如何氟葡萄糖胺抑制效应白细胞的亲皮活性，并确定是否氟糖影响白细胞粘附分子的功能参与其他非皮肤迁移模式。将采用许多使用新鲜和培养的白细胞的生化方法来研究氟葡糖胺如何修饰白细胞聚糖的表达和功能。将使用明确定义的炎症模型分析氟葡萄糖胺对效应皮肤和非皮肤归巢白细胞亚群的疗效和特异性。本临床前研究的总体目标是显示氟葡萄糖胺如何作为皮肤炎症的免疫调节剂，从而深入了解CAM葡萄糖胺对白细胞归巢受体的潜在功效。 公共卫生相关性。氟代糖抗炎活性的机理分析项目叙述我们的实验室最近已经表明，葡萄糖胺的氟代糖类似物在皮炎模型中引起抗炎活性。本项目的总体目标是了解氟葡萄糖胺如何抑制白细胞向发炎皮肤的运输。我们的临床前研究将证明氟葡萄糖胺作为皮肤炎症免疫调节剂的效用，并可能帮助模拟补充和替代药物（如葡萄糖胺）的作用。

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.