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)：循环中的suPAR在FSGS局灶性节段性肾小球硬化(FSGS)中的作用FSGS是一种以足细胞损伤、蛋白尿和进行性肾衰为特征的严重肾小球疾病，该疾病在移植后30%的成年人中可能复发，在儿童中的比例甚至更高。最近发现，大多数FSGS患者血清中的可溶性尿激酶型纤溶酶原激活剂受体(SuPAR)水平升高。动物实验表明，suPAR通过激活足细胞β3整合素，引起啮齿动物足细胞损伤和FSGS类型改变。由于suPAR水平的升高是由于变量，如癌症或感染；并不经常出现蛋白尿，这项建议试图定义suPAR的确切形式(S)是/正在发挥作用的局灶性节段性肾小球硬化(FGS)的致病因素。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所致。在这项拨款申请下，我们检验了一种假设，即只有特定形式的suPAR(S)，即低糖基化形式(S)，才是导致FSGS的原因。目的1鉴定FSGS患者suPAR的病理形态(S)。目的2将在小鼠身上测试病理性suPAR。AIM 3的目标是开发一种更具特异性的ELISA测试，AIM 4将评估Beta 3基因中可能允许足细胞整合素过度激活的常见遗传变异(P1A2)的风险。总而言之，这项研究计划可能会揭开FSGS的一个主要原因，并可能导致对这种疾病患者的精细化治疗。