PATHOGENESIS OF ALPORT SYNDROME

阿尔波特综合征的发病机制

基本信息

批准号：
8853478
负责人：
George Jarad
金额：
$ 22.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8853478
关键词：
Address Adolescent Affect Age Agrin Albumins Albuminuria Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animals Appearance Biopsy Canis familiaris Cells Child Chronic Kidney Failure Cicatrix Collagen Type IV Data Defect Detection Development Diagnosis Disease Disease Progression Early Diagnosis End stage renal failure Epithelial Cells Exhibits Extracellular Matrix Family Fibrosis Filtration Foot Process Future Genes Genetic Genomics Glomerulonephritis Goals Health Hearing Hematuria Heparan Sulfate Proteoglycan Hereditary nephritis Human In Vitro Inherited Injury Kidney Kidney Diseases Kidney Failure Laminin Lead Longevity Mediating Messenger RNA Methods MicroRNAs Modeling Mus Mutation Newborn Infant Nidogen Outcome Study Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Plasma Proteins Prevalence Proteins Publishing Ramipril Recording of previous events Renal Replacement Therapy Renal function Renal glomerular disease Renin-Angiotensin System Signal Pathway Signal Transduction Site Skin Symptoms Syndrome Testing Therapeutic Tubular formation alternative treatment cell injury glomerular basement membrane glomerular filtration glomerulosclerosis improved in vivo inhibitor/antagonist interest kidney cell mouse model new therapeutic target novel null mutation outcome forecast podocyte prevent research study standard of care therapy design tool

项目摘要

DESCRIPTION (provided by applicant): Kidney disease is worldwide health problem that is becoming increasingly common. Primary glomerular disease, both genetic and acquired, represents a significant proportion of cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged, leaky to plasma proteins, and eventually non-functional. Our focus has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the filtration barrier to albumin. The GBM contains collagen IV, laminin, nidogen, and the heparan sulfate proteoglycan agrin. Mutations that affect the collagen IV component of the GBM cause Alport syndrome, or hereditary glomerulonephritis, which leads to end-stage renal disease (ESRD). The prevalence of Alport syndrome has been estimated to be 1 in 5,000 to 1 in 50,000 newborns, so there are many thousands of affected patients around the world. Structural abnormalities lead to thickening and splitting of the GBM and eventually foot process effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Until recently there had been no specific treatment for Alport syndrome. However, studies in mice and dogs had shown that ACE inhibition slows kidney disease progression to ESRD. These animal studies have been validated in human Alport syndrome, for which ACE inhibitors are now considered the standard of care. Despite this treatment breakthrough, 1) the mechanisms by which ACE inhibition slows kidney disease progression is unclear; and 2) it is still not a cure for Alport syndrome. Our preliminary data show that Alport mice with a null mutation in the albumin gene (Alb) exhibit reduced glomerulosclerosis and tubulointerstitial disease and have a prolonged lifespan. This suggests the hypothesis that albumin is injurious to podocytes and/or tubular epithelial cells by activating specific albumin-induced injury signaling pathways. The major goal of this proposal is to identify these pathways at a mechanistic level by focusing on a detailed characterization of Alport mice with and without ACEi and with levels of albumin that are normal, reduced, or zero. Identification of these injury pathways will provide novel therapeutic targets that can be modulated in parallel to inhibition of the renin-angiotensin system to further slow/inhibit progression to ESRD in Alport syndrome patients. Another important outcome of this study will be an improved understanding of the mechanism of action of ACE inhibition, whether it is effective at slowing progression to ESRD solely due to reduction in albuminuria or whether other mechanisms are involved. Our results could have important implications for understanding and treating patients with Alport syndrome and perhaps those with other kidney diseases.

描述（由申请人提供）：肾脏疾病是一个日益普遍的世界性健康问题。原发性肾小球疾病（遗传性和获得性）占病例的很大比例。我们有兴趣了解肾小球滤过屏障的构成以及它如何受损、渗漏血浆蛋白并最终失去功能。我们的重点是研究肾小球基底膜 (GBM) 的组成和功能，肾小球基底膜是一种特殊的细胞外基质，是白蛋白过滤屏障的组成部分。 GBM 含有 IV 型胶原蛋白、层粘连蛋白、巢蛋白和硫酸乙酰肝素蛋白聚糖集聚蛋白。影响 GBM 的 IV 型胶原蛋白成分的突变会导致 Alport 综合征或遗传性肾小球肾炎，从而导致终末期肾病 (ESRD)。据估计，阿尔波特综合征的患病率为五千分之一到五万分之一的新生儿，因此全世界有数千名患者受到影响。结构异常导致 GBM 增厚和分裂，最终导致足突消失、肾小球硬化和肾小管间质纤维化。直到最近，阿尔波特综合征还没有具体的治疗方法。然而，对小鼠和狗的研究表明，ACE 抑制可减缓肾脏疾病进展为 ESRD。这些动物研究已在人类阿尔波特综合征中得到验证，ACE 抑制剂现在被认为是该综合征的标准治疗方法。尽管取得了这一治疗突破，1) ACE 抑制减缓肾脏疾病进展的机制尚不清楚； 2）它仍然不能治愈阿尔波特综合征。我们的初步数据表明，白蛋白基因 (Alb) 无效突变的 Alport 小鼠表现出肾小球硬化和肾小管间质疾病减少，并且寿命延长。这表明白蛋白通过激活足细胞和/或肾小管上皮细胞而损害足细胞和/或肾小管上皮细胞的假设特定白蛋白诱导的损伤信号通路。该提案的主要目标是通过重点关注具有和不具有 ACEi 以及白蛋白水平正常、降低或为零的 Alport 小鼠的详细特征，在机制水平上识别这些途径。这些损伤途径的识别将提供新的治疗靶点，可以在抑制肾素-血管紧张素系统的同时进行调节，以进一步减缓/抑制 Alport 进展为 ESRD 综合症患者。这项研究的另一个重要成果将是更好地了解 ACE 抑制的作用机制，无论它是否仅由于蛋白尿减少而有效减缓 ESRD 进展，还是涉及其他机制。我们的结果可能对理解和治疗阿尔波特综合征患者以及其他肾脏疾病患者具有重要意义。