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.

局灶节段性肾小球硬化（Focal Segmental glomerullosclerosis， FSGS）是一种以足细胞损伤、蛋白尿和进行性肾功能下降为特征的严重肾小球疾病，成人移植后复发率为30%，儿童复发率更高。近年来，在大多数FSGS患者血清中发现可溶性尿激酶纤溶酶原激活物受体（suPAR）升高。动物实验表明，suPAR通过激活足细胞β 3整合素引起足细胞损伤和fsgs型改变。由于癌症或感染等变量，suPAR水平升高；并且不经常出现蛋白尿，本提案旨在确定作为局灶节段性肾小球硬化（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suPAR的不同形式。在这项拨款申请中，我们检验假设只有特定形式的suPAR（即低糖基化形式）负责FSGS。目的1将确定FSGS患者suPAR的病理形式。目的2检测小鼠病理suPAR。Aim 3旨在开发一种更具体的ELISA测试，Aim 4将评估β 3基因中常见遗传变异（P1A2）的风险，该基因可能会导致足细胞中整合素的过度激活。总而言之，这项研究计划将有可能揭示FSGS的主要原因，并可能为该病患者提供更精确的治疗方法。