Modulation of IgG blood-brain barrier permeability by surface-accessible glycan moieties

通过表面可及的聚糖部分调节 IgG 血脑屏障通透性

• 批准号: 8872573
• 负责人: WILLIAM A BANKS
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872573
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Blood - brain barrier anatomy; Brain; Carbohydrates; Central Nervous System Diseases; Clinical Trials; Detection; Ensure; Face; Galactose; Glycoproteins; Human; Immune; Immunoglobulin G; In Vitro; Infusion procedures; Intravenous Immunoglobulins; Iodine; Lectin; Measures; Methodology; Methods; Modeling; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Outcome; Pathway interactions; Patients; Penetration; Peripheral; Permeability; Pharmaceutical Preparations; Polysaccharides; Radiolabeled; Role; Sialic Acids; Surface; Surface Plasmon Resonance; Testing; Therapeutic antibodies; Tissues; Transgenic Mice; Work; functional decline; in vitro Model; peptide A; public health relevance; radiotracer; response; sialylation; therapeutic target

 DESCRIPTION (provided by applicant): Here, we will test the hypothesis that IgG antibody blood-brain barrier permeability will increase in response to elevated surface sialic acid levels. Increasing the blood-brain barrier permeability of antibodies is important because antibody drugs for Alzheimer's Disease and other neurodegenerative disorders remain largely outside the brain after administration. Increasing antibody concentrations in the brain will help the antibodies access their primary therapeutic targets and may also tap into new immune pathways that benefit patients. The project consists of two aims that each address a question below: (1) Does the average IgG blood-brain barrier permeability increase upon addition of IgG sialic acid? (2) Is the blood-brain barrier permeability specific for sialylated IgG higher than fo desiaylated IgG? Both aims will use in vitro blood-brain barrier models to ensure that blood-brain barrier permeability is measured in the absence of other influx and efflux pathways. Aim 1 uses a standard radiolabelling methodology for IgG detection. Aim 2 uses a glycan-specific Surface Plasmon Resonance method to specifically track IgG with surface exposed sialic acid or galactose moieties. Support for this hypothesis will open new avenues for antibody treatment of Alzheimer's Disease and other diseases of the central nervous system.

 描述（由适用提供）：在这里，我们将检验以下假设：IgG抗体血脑屏障的渗透性会因表面唾液酸水平升高而增加。抗体的血脑屏障渗透性增加很重要，因为阿尔茨海默氏病和其他神经退行性疾病的抗体药物在给药后仍在大脑之外。大脑中抗体浓度的升高将有助于抗体获得其主要的治疗靶标，并且还可以利用有益于患者的新免疫途径。该项目由两个目的组成，每个目标都解决了以下问题：（1）加入IgG唾液酸后，平均IgG血脑屏障渗透性会增加吗？ （2）对溶解的IgG的血脑屏障渗透性是否高于Fo deiaylated IgG？这两个目标都将使用体外血脑屏障模型，以确保在没有其他影响和外排途径的情况下测量血脑屏障的渗透性。 AIM 1使用标准的辐射标记方法进行IgG检测。 AIM 2使用聚糖特异性的表面等离子体共振法特异性地跟踪具有表面暴露的唾液酸或半乳糖部分的IgG。对这一假设的支持将为阿尔茨海默氏病和中枢神经系统的其他疾病的抗体治疗开辟新的途径。