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: 9069723
• 负责人: WILLIAM A BANKS
• 金额: $ 7.29万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069723
• 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; Health; 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; 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(由申请人提供)：在这里，我们将测试假设，即免疫球蛋白抗体血脑屏障通透性将增加，以响应表面唾液酸水平升高。增加抗体的血脑屏障渗透性很重要，因为治疗阿尔茨海默病和其他神经退行性疾病的抗体药物在给药后大部分仍留在大脑之外。增加大脑中的抗体浓度将有助于抗体进入其主要治疗靶点，并可能进入新的免疫途径，使患者受益。该项目由两个目标组成，每个目标都解决了以下问题：(1)添加唾液酸后，平均免疫球蛋白血脑屏障通透性是否增加？(2)唾液酸化的免疫球蛋白的血脑屏障通透性是否高于预期的免疫球蛋白？这两个目标都将使用体外血脑屏障模型，以确保在没有其他流入和流出途径的情况下测量血脑屏障的渗透性。AIM 1使用标准的放射性标记方法检测免疫球蛋白。目的2利用一种糖链特异性的表面等离子体共振法，以表面暴露的唾液酸或半乳糖基团来特异性地追踪免疫球蛋白。支持这一假说将为阿尔茨海默病和其他中枢神经系统疾病的抗体治疗开辟新的途径。