Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars

氟糖抗炎活性的机制分析

基本信息

批准号：
7584425
负责人：
CHARLES J DIMITROFF
金额：
$ 41.5万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7584425
关键词：
Acetylglucosamine Acute Graft Versus Host Disease Adherence Adhesions Adhesives Affect Allergic Contact Dermatitis Anti-Inflammatory Agents Anti-inflammatory Arthritis Atopic Dermatitis Attenuated Autoimmunity Binding Biochemical Biological Assay Blood Vessels Carbohydrates Cell Adhesion Molecules Cells Chemotaxis Complementary and alternative medicine Cutaneous Data Dermal Dermatitis Dose Drug Formulations E-Selectin Endothelium Event Exhibits Flow Cytometry Galectin 1 Glucosamine Goals Grant Immunoblotting Immunomodulators In Vitro Individual Inflammation Inflammatory Response Integrins Investigation Kinetics L-Selectin Laboratories Lectin Leukocyte Adhesion Molecules Leukocyte Trafficking Leukocyte-Adhesion Receptors Leukocytes Ligands Malignant Neoplasms Mediating Membrane Proteins Metabolic Metabolism Modality Modeling Mus N-acetyllactosamine National Center for Complementary and Alternative Medicine Natural Killer Cells Outcome P-Selectin Pathogenesis Pattern Polysaccharides Psoriasis Publishing Reporting Selectins Skin Specificity Structure T-Lymphocyte Therapeutic alternative treatment analog carbohydrate biosynthesis carbohydrate metabolism carbohydrate structure cell motility chemokine receptor glycosyltransferase granulocyte immunoregulation improved in vivo inhibitor/antagonist innovation insight leukemia leukocyte homing migration mimetics mouse model pre-clinical public health relevance receptor receptor binding receptor function research study skin disorder sugar

项目摘要

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.

描述（由申请人提供）：血清细胞对皮肤的运输是由血管内皮选择蛋白和白细胞Selectin配体之间的粘合剂相互作用指导的。白细胞选择配体活性由白细胞表面蛋白上的专门碳水化合物结构赋予。这些在白细胞不同亚集的专门碳水化合物赋予白细胞进入皮肤的能力，因此被称为皮肤亲切受体。为此，控制与皮肤疾病相关的皮肤白细胞的迁移，例如特应性皮炎，过敏性皮炎，牛皮癣和皮肤白血病，并具有选择的糖含量糖含糖的糖含量代表一种潜在的治疗疗法。据称，非处方葡萄糖胺制剂的作用是为了缓解关节炎的条件，并支持了这一概念。我们实验室的初步数据表明，天然葡萄糖的简单氟葡萄糖类似物（或氟葡萄糖胺）调节白细胞选择蛋白配体活性所需的碳水化合物结构，从而导致皮肤炎症性皮肤炎性衰减。我们假设这种氟葡萄糖胺类似物可以用作辅助和替代药用（CAM）剂（例如葡萄糖胺）的模型，以研究效应子白细胞上的聚糖如何和哪些聚糖对聚糖 - 代谢抑制作用敏感。本应用中的研究目标是1.）定义氟葡萄糖胺对白细胞选择配体和其他粘附分子表达和2.）的机制。我们的目的是提高对氟葡萄糖胺如何抑制效应子白细胞的皮肤核活性，并确定氟糖是否影响白细胞粘附分子功能涉及其他非皮肤迁移模式。使用新鲜和培养的白细胞的多种生化方法将用于研究氟葡萄胺如何修饰白细胞聚糖表达和功能。使用明确定义的炎症模型，将对效应的皮肤和非皮肤白细胞亚群分析氟葡萄糖胺的功效和特异性。这项临床前研究的总体目的是展示氟葡萄糖胺如何作为皮肤炎症的免疫调节剂，从而深入了解白细胞托管受体对潜在的CAM葡萄糖胺功效。公共卫生相关性。氟胡子项目叙事的抗炎活性的机理分析我们的实验室最近表明，葡萄糖胺的氟化糖类似物在皮肤炎模型中引起抗炎活性。该项目的总体目的是了解氟葡萄糖如何抑制白细胞对皮肤发炎的运输。我们的临床前研究将证明氟葡萄糖胺作为皮肤炎症的免疫调节剂的实用性，并可能有助于通过互补和替代药物（例如葡萄糖胺）对影响进行建模。