Nephritogenic autoantibodies in systemic lupus

系统性狼疮中的肾炎性自身抗体

• 批准号: 9034312
• 负责人: Dawn Caster
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-25 至 2021-02-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034312
• 关键词: Accounting; Actins; Address; Affect; American; Animal Model; Annexins; Antibodies; Antigen Targeting; Antigen-Antibody Complex; Attention; Autoantibodies; Autoimmune Diseases; Award; Biological Markers; Cell physiology; Cells; Clinical; Cytoskeleton; Data; Deposition; Development; Development Plans; Dialysis procedure; Discipline; Disease; End stage renal failure; Evaluation; Filtration; Functional disorder; Goals; Histopathology; Human; Immunoglobulin G; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; K-Series Research Career Programs; Kidney; Kidney Failure; Knowledge; Lead; Life; Lupus; Lupus Nephritis; Membranous Glomerulonephritis; Mentors; Mentorship; Nuclear; Nucleosomes; Pathogenesis; Patients; Physicians; Prognostic Marker; Proteins; Proteinuria; Publications; Renal glomerular disease; Research; Role; Scientist; Serum; Systemic Lupus Erythematosus; Testing; Therapeutic immunosuppression; Time; Tissues; Training; Treatment Protocols; Validation; base; career; career development; diagnostic biomarker; disease diagnosis; ds-DNA; experience; improved; improved outcome; injured; lupus prone mice; mesangial cell; moesin; mouse model; novel diagnostics; podocyte; programs; public health relevance; research study; skills; treatment response

 DESCRIPTION (provided by applicant): Up to 60% of SLE patients develop clinical evidence of kidney injury, termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells, leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes, of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure. Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies, diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases, including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins, including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins, including annexin A2 and moesin, result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN, validation of those autoantibodies as biomarkers for disease, examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies, and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens, this will lead to improved understanding of the pathogenic mechanisms of disease, and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist, investigating clinical and basic aspects of lupus nephritis, through an individualized career development plan which has been developed by the mentorship team.

 描述（由申请人提供）：高达60%的SLE患者出现肾损伤的临床证据，称为狼疮性肾炎（LN）。LN被认为是由肾小球免疫复合物沉积激活损伤肾小球细胞的炎性级联反应引起的，导致蛋白尿和滤过能力丧失。LN根据肾组织病理学分为SI类，其中增殖性LN（ISN/RPS III或IV类）最可能引起肾衰竭。 大多数研究增殖性LN的原因集中在抗核抗体的致肾炎潜力，转移注意力从组织/细胞特异性自身抗体的潜在作用。越来越多的证据表明，组织特异性靶抗原的自身抗体有助于许多肾小球疾病，包括LN的发病机制。我们的初步数据显示，增生性LN患者的血清中含有抗人肾小球蛋白的自身抗体，包括膜联蛋白A2和膜突蛋白。这些发现支持了我们的中心假设，即针对肾小球蛋白（包括膜联蛋白A2和膜突蛋白）的自身抗体导致免疫复合物沉积，导致增殖性LN。这个指导的职业发展建议将集中在增殖性LN中膜联蛋白A2和膜突蛋白的自身抗体的进一步表征，这些自身抗体作为疾病生物标志物的验证，暴露于这些自身抗体的足细胞和系膜细胞的功能变化的检查，以及这些抗体在动物模型中的致肾炎潜力的评估。正如在识别靶抗原后对原发性膜性肾病的理解的进展所证明的那样，这将导致对疾病的致病机制的更好理解，并提供新的诊断和预后生物标志物。该指导职业发展奖还将为申请人提供受保护的时间，以发展成为独立的医生科学家所需的技能，通过指导团队制定的个性化职业发展计划调查狼疮肾炎的临床和基本方面。