Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars

描述（由申请人提供）：白细胞到皮肤的运输是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在不同的白细胞亚群上表达，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来控制与皮肤疾病（如特应性皮炎、过敏性皮炎、银屑病和皮肤白血病）相关的皮肤定位白细胞的迁移是一种潜在的有前途的治疗策略。非处方氨基葡萄糖制剂的作用被认为可以缓解关节炎，并支持这一观点。我们实验室的初步数据表明，天然葡萄糖胺的简单氟化葡萄糖胺类似物（或氟-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-氨基葡萄糖类似物可以用作补充和替代药物（CAM）药物（如氨基葡萄糖）的模型，以研究效应白细胞上的哪些聚糖如何以及对糖代谢抑制敏感。本应用程序的研究目标是1.)明确氟氨基葡萄糖对白细胞选择素配体等粘附分子表达的作用机制；探讨氟氨基葡萄糖治疗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趋肤活性的理解，并确定氟糖是否影响涉及其他非皮肤迁移模式的白细胞粘附分子功能。许多使用新鲜和培养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聚糖的表达和功能。氟氨基葡萄糖的功效和特异性将分析效应皮肤和非皮肤归巢白细胞亚群使用明确定义的炎症模型。这项临床前研究的总体目标是显示氟氨基葡萄糖如何作为皮肤炎症的免疫调节剂，为CAM氨基葡萄糖对白细胞归一受体的潜在功效提供见解。

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.