Innovative Approaches to Treating Alport Syndrome

项目摘要 肾脏疾病是世界范围内的健康问题，正变得越来越普遍。原发性肾小球 遗传性和后天性疾病在病例中占很大比例。我们有兴趣 了解肾小球滤过屏障的组成，以及它是如何受损，渗漏， 血浆蛋白质，最终失去功能。我们的重点一直是调查的组成和 肾小球基底膜（GBM）是一种特化的细胞外基质， 肾脏滤过屏障的组成部分。GBM含有胶原蛋白IV、层粘连蛋白、巢蛋白和 硫酸乙酰肝素蛋白聚糖聚集蛋白，以及可能的几十种其它不太丰富的基质蛋白。虽然 肾小球基底膜由足细胞和肾小球内皮细胞合成，仅由足细胞合成 这使得主要的胶原蛋白IV亚型，其中包括α 3，α 4和α 5链，组装， 形成分泌的异源三聚体。影响GBM的IV型胶原成分的突变导致Alport 综合征，导致终末期肾病（ESKD）以及听力和视力缺陷。的 Alport综合征的患病率估计为1/5，000至10，000新生儿，因此， 世界各地成千上万的受影响患者。继发于以下疾病的结构性GBM异常 胶原IV缺陷导致GBM增厚和分裂，最终导致足细胞足突 消失、肾小球硬化和肾小管间质纤维化。直到最近还没有治疗方法 奥尔波特综合征然而，对小鼠和狗的研究表明，ACE抑制剂减缓了肾功能， 疾病进展为ESKD。这些动物研究已在人类Alport综合征中得到验证 ACE抑制剂或血管紧张素II受体阻滞剂现在被认为是标准治疗的患者， 在乎尽管这一治疗突破延迟了ESKD，但它并不是一种治愈方法;仍然需要新的治疗方法。 靶向治疗。该提案的目标是使用创新的最先进技术， 小分子，遗传和蛋白质生物化学方法，试图恢复Alport GBM 转化为某种程度上正常的组成或通过去除致病成分来改变其组成。 在任何一种情况下，预期改善GBM组成将至少部分地使GBM正常化 结构和功能。与作为标准治疗的肾素-血管紧张素系统阻断剂一起， 治疗应大大延迟ESKD的时间，并对患者有益。

Project Summary 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 kidney’s filtration barrier. The GBM contains collagen IV, laminin, nidogen, and the heparan sulfate proteoglycan agrin, and likely dozens of other less abundant matrix proteins. Although the GBM is synthesized by both podocytes and glomerular endothelial cells, it is exclusively podocytes that make the major collagen IV isoform, which consists of the 3, 4, and 5 chains that assemble to form a secreted heterotrimer. Mutations that affect this collagen IV component of the GBM cause Alport syndrome, which leads to end-stage kidney disease (ESKD) as well as hearing and eye defects. The prevalence of Alport syndrome has been estimated to be 1 in 5,000 to 10,000 newborns, so there are hundreds of thousands of affected patients around the world. Structural GBM abnormalities secondary to the collagen IV defect lead to thickening and splitting of the GBM and eventually podocyte foot process effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Until recently there has been no treatment for Alport syndrome. However, studies in mice and dogs had shown that ACE inhibition slows kidney disease progression to ESKD. These animal studies have been validated in human Alport syndrome patients, for whom ACE inhibitors or angiotensin II receptor blockers are now considered the standard of care. Despite this treatment breakthrough that delays ESKD, it is not a cure; there is still a need for new targeted therapies. The goal of this proposal is to use innovative, state of the art technologies that involve small molecule, genetic, and protein biochemistry approaches to attempt to either restore the Alport GBM to a somewhat normal composition or to alter its composition through removal of pathogenic components. In either case, the expectation is that improving GBM composition will at least partially normalize GBM structure and function. Together with renin-angiotensin system blockade as a standard of care, these treatments should greatly delay the time to ESKD and be beneficial for patients.