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.