IgA1 glycosylation and receptor interactions in IgA nephropathy

IgA 肾病中 IgA1 糖基化和受体相互作用

• 批准号: 7915865
• 负责人: ANDREW B HERR
• 金额: $ 14.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915865
• 关键词: Address; Adsorption; Affect; Affinity; Antibodies; Antigen-Antibody Complex; Binding; Biological Assay; Blood; Caring; Cell Proliferation; Cells; Characteristics; Complex; Conflict (Psychology); Data; Deposition; Dialysis procedure; Disease; End stage renal failure; Event; Extravasation; Feasibility Studies; Fourier transform ion cyclotron resonance; Functional disorder; Glomerulonephritis; Glycoside Hydrolases; Goals; Homeostasis; IgA receptor; IgA1; Immune; Immunoglobulin A; Immunoglobulins; Infiltration; Inflammatory; Inflammatory Response; Insecta; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Lectin; Mammalian Cell; Mass Spectrum Analysis; Medical; Modification; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Patients; Pattern; Play; Polysaccharides; Principal Investigator; Proteins; Recombinants; Renal function; Reporting; Research; Research Personnel; Role; Sampling; Serum; Source; Structure; Structure of glomerular mesangium; Surface Plasmon Resonance; Techniques; Testing; Therapeutic; Transferrin Receptor; United States; Urine; Wages; Work; analytical ultracentrifugation; base; combat; cost; glycosylation; inhibitor/antagonist; interest; mesangial cell; physical property; polymerization; polypeptide; programs; receptor; receptor binding; research study; therapeutic development

DESCRIPTION (provided by applicant): IgA nephropathy (IgAN) is the most common form of glomerulonephritis, an inflammatory disease of the kidney. IgAN is characterized by deposition of lgA1 antibodies in the glomerular mesangium of the kidney, followed by infiltration of inflammatory immune cells and eventual loss of kidney function. lgA1 antibodies show altered glycosylation and polymerization states in a large percentage of IgAN patients. These alterations have been suggested to play a role in modifying the interactions between lgA1 and IgA-specific receptors, particularly, FcalphaRI (CD89) and transferrin receptor (TfR), although conflicting data have been reported. The long-term goal of this research effort is to ascertain the precise molecular events that lead to lgA1 deposition in the mesangium. The central hypothesis is that modifications in lgA1 glycosylation and polymerization lead to increased affinity for critical IgA-binding receptors (specifically, FcalphaRI and TfR). These aberrant interactions are proposed to lead directly to deposition of lgA1 in the kidney mesangium and the ensuing inflammatory response. Specific Aims for this proposal include: 1) Characterize the effects of lgA1 glycosylation and polymerization on its interaction with FcalphaRI and TfR, using recombinant lgA1 with defined glycosylation states; 2) Characterize the receptor interactions of lgA1 purified from serum of healthy and IgAN patients and correlate the receptor affinity with lgA1 glycosylation and polymerization state; and 3) Determine the contribution of FcalphaRI N-glycosylation to its interaction with lgA1 and TfR. Binding studies with lgA1, FcalphaRI, and TfR will be carried out by surface plasmon resonance and analytical ultracentrifugation. lgA1 glycosylation will be characterized by lectin affinity assays along with thorough analysis of samples of interest by Fourier transform-ion cyclotron resonance mass spectrometry. This research will help determine the molecular basis for IgA nephropathy (IgAN), a kidney disease affecting approximately 100,000 patients in the US. IgAN is a primary cause of end-stage renal disease, which costs $18 billion per year in medical care. Understanding the molecular interactions underlying IgAN will be the first step towards developing treatments for this costly and debilitating disease.

描述（由申请人提供）：Iga肾病（Igan）是肾小球肾炎的最常见形式，是肾脏的炎症性疾病。 Igan的特征是LGA1抗体在肾脏的肾小球肾小球中沉积，然后浸润炎性免疫细胞和最终的肾功能丧失。 LGA1抗体显示大部分IGAN患者的糖基化和聚合态的改变。尽管已经报道了相互冲突的数据，但已经提出了这些变化在修改LGA1和IGA特异性受体之间的相互作用中发挥作用，尤其是FCalphari（CD89）和转铁蛋白受体（TFR）。这项研究工作的长期目标是确定导致Mesangium中LGA1沉积的精确分子事件。中心假设是LGA1糖基化和聚合的修饰会导致对关键IgA结合受体的亲和力增加（特别是FCalphari和TFR）。提出这些异常相互作用直接导致LGA1在肾脏中的沉积和随后的炎症反应。该建议的具体目的包括：1）使用重组LGA1与定义的糖基化态，表征LGA1糖基化和聚合对其与FCalphari和TFR相互作用的影响； 2）表征从健康和Igan患者的血清纯化的LGA1的受体相互作用，并将受体亲和力与LGA1糖基化和聚合状态相关联； 3）确定FCalphari N-糖基化对其与LGA1和TFR相互作用的贡献。 LGA1，FCALPHARI和TFR的结合研究将通过表面等离子体共振和分析性超速离心进行。 LGA1糖基化的特征是凝集素亲和力测定以及通过傅立叶转化离子环共振质谱法对感兴趣的样品进行彻底分析。这项研究将有助于确定IGA肾病（IGAN）的分子基础，这是一种影响美国约100,000例患者的肾脏疾病。伊甘（Igan）是终末期肾脏疾病的主要原因，每年的医疗服务费用为180亿美元。了解Igan的分子相互作用将是为这种昂贵和使人衰弱的疾病开发治疗方法的第一步。