Role of Circulating suPAR in FSGS

循环 suPAR 在 FSGS 中的作用

• 批准号: 8882417
• 负责人: Jochen Reiser
• 金额: $ 51.31万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882417
• 关键词: Actins; Adult; Affect; Animal Experiments; Antibodies; Applications Grants; Bacteria; Biochemical; Biological; Biological Assay; Blood; Blood Circulation; Blood Platelets; Cell Culture Techniques; Cells; Child; Clinical; Codon Nucleotides; Data; Development; Diagnosis; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Fluorescence Microscopy; Focal Segmental Glomerulosclerosis; Follow-Up Studies; Foot Process; General Population; Genes; Genetic Polymorphism; Goals; Grant; Health; Heterogeneity; Human; In Vitro; Infection; Injection of therapeutic agent; Injury; Insecta; Integrin Inhibition; Integrin beta3; Integrins; Kidney; Kidney Diseases; Lead; Length; Leucine; Malignant Neoplasms; Measures; Mediating; Molecular; Mus; Nature; Pathogenesis; Pathologic; Patients; Permeability; Plant Roots; Plasma; Proline; Proteins; Proteinuria; Recombinant Proteins; Recurrence; Renal glomerular disease; Research; Risk; Rodent; Role; Serum; Signal Transduction; Stratification; Stream; Structure; Sum; Testing; Transcript; Transplantation; Urokinase Plasminogen Activator Receptor; base; genetic variant; glycosylation; human EMS1 protein; improved; in vivo; novel; novel therapeutics; outcome forecast; podocyte; programs; research and development; research study; small molecule; src-Family Kinases

DESCRIPTION (provided by applicant): Role of Circulating suPAR in FSGS Focal Segmental Glomerulosclerosis (FSGS) is a severe glomerular disease that is characterized by podocyte injury, proteinuria and progressive renal decline, the disease is likely to recur after transplantation in 30% of adults and even in higher number in children. Recently, soluble urokinase plasminogen activator receptor (suPAR) has been found to be elevated in the serum of the majority of patients with FSGS. Animal experiments suggested that suPAR caused podocyte injury and FSGS-type changes in rodents through activation of podocyte beta 3 integrin. As suPAR levels are increased due to variables, such as cancer or infection; and do not routinely present with proteinuria, this proposal seeks to define the precise form (s) of suPAR that is/are acting as a causative factor for focal segmental glomerulosclerosis (FSGS). We hypothesize that diverse effects of suPAR in different diseases are due to different forms of suPAR. Under this grant application we test hypothesis that only the specific form(s) of suPAR, i.e. hypoglycosylated form(s), is (are) responsible for FSGS. Aim 1 will identify pathological form(s) of suPAR in FSGS patients. Aim 2 will test pathological suPAR in mice. Aim 3 will be aimed to develop a more specific ELISA test and Aim 4 will assess the risk of a common genetic variant (P1A2) in the beta 3 gene that might allow integrin hyperactivation in podocytes. In sum, this research program will potentially unravel a major cause of FSGS and might lead to a refined treatment for patients with the disease.

描述（申请人提供）：循环suPAR在FSGS中的作用 局灶性节段性肾小球硬化症（FSGS）是一种严重的肾小球疾病，其特征是足细胞损伤、蛋白尿和进行性肾功能衰退，30%的成人移植后该疾病可能复发儿童中的比例甚至更高。最近，发现大多数 FSGS 患者血清中可溶性尿激酶纤溶酶原激活剂受体 (suPAR) 升高。动物实验表明，suPAR 通过激活足细胞 β 3 整合素，引起啮齿动物足细胞损伤和 FSGS 型变化。由于癌症或感染等变量，suPAR 水平会升高；并且通常不会出现蛋白尿，该提案旨在定义作为局灶节段性肾小球硬化症 (FSGS) 致病因素的 suPAR 的精确形式。我们假设 suPAR 在不同疾病中的不同作用是由于不同形式的 suPAR 造成的。在本次拨款申请中，我们测试了以下假设：只有特定形式的 suPAR（即低糖基化形式）才对 FSGS 负责。目标 1 将确定 FSGS 患者中 suPAR 的病理形式。目标 2 将在小鼠中测试病理性 suPAR。目标 3 将旨在开发一种更具体的 ELISA 测试，目标 4 将评估 β 3 基因中常见遗传变异 (P1A2) 的风险，该变异可能导致足细胞中整合素过度激活。总之，该研究项目将有可能揭示 FSGS 的主要原因，并可能为该疾病患者提供更完善的治疗方法。