Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars

描述(申请人提供)：白细胞向皮肤的运输是由血管内皮细胞选择素和白细胞选择素配体之间的粘附性相互作用引导的。白细胞选择素配体的活性是由白细胞表面蛋白上显示的特殊碳水化合物结构赋予的。这些特殊的碳水化合物表达在不同的白细胞亚群上，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，利用选择素配体修饰的糖模拟物控制与皮肤疾病相关的皮肤归巢白细胞的迁移，如特应性皮炎、过敏性皮炎、牛皮癣和皮肤白血病，是一种潜在的有前途的治疗策略。非处方药氨基葡萄糖制剂的效果一直被认为可以缓解关节炎，并支持这一概念。我们实验室的初步数据显示，天然氨基葡萄糖的简单氟化氨基葡萄糖类似物(或氟氨基葡萄糖)调节白细胞选择素配体活性所需的碳水化合物结构，导致减弱皮肤炎症反应。我们假设，这种氟氨基葡萄糖类似物可以作为补充和替代药物(CAM)的模型，如氨基葡萄糖，以研究效应细胞上的哪些多糖如何以及哪些糖链对糖代谢抑制敏感。本申请的研究目标为1。)明确氟氨基葡萄糖对白细胞、选择素配体等黏附分子表达的作用机制。目的：研究氟氨基葡萄糖对小鼠炎症模型的体内疗效和特异性。我们的目的是提高我们对氟氨基葡萄糖如何抑制效应白细胞的亲皮活性的理解，并确定氟糖是否影响参与其他非皮肤迁移模式的白细胞黏附分子功能。许多使用新鲜和培养的白细胞的生化方法将被用来研究氟氨基葡萄糖如何改变白细胞的多糖表达和功能。将使用明确的炎症模型分析氟氨基葡萄糖对效应者皮肤和非皮肤归巢白细胞亚群的有效性和特异性。这项临床前研究的总体目标是展示氟氨基葡萄糖如何作为皮肤炎症的免疫调节剂，为了解CAM氨基葡萄糖对白细胞归巢受体的潜在疗效提供洞察。 与公共卫生相关。氟糖抗炎活性的机制分析项目简介我们的实验室最近发现，氨基葡萄糖的氟化糖类似物在皮炎模型中具有抗炎活性。这个项目的总体目标是了解氟氨基葡萄糖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氨基葡萄糖作为皮肤炎症的免疫调节剂的效用，并潜在地帮助模拟补充和替代药物的效果，如氨基葡萄糖。

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.