Innovative Approaches to Treating Alport Syndrome

项目摘要 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 遗传病和获得性疾病在病例中占很大比例。我们感兴趣的是 了解肾小球滤过屏障的组成以及它是如何受损的，泄漏到 血浆蛋白，并最终失去功能。我们的重点是调查它的成分和 肾小球基底膜(GBM)是一种特殊的细胞外基质，是一种 肾脏滤过屏障的组成部分。基底膜含有IV型胶原、层粘连蛋白、尼德原和 硫酸乙酰肝素蛋白多糖凝集蛋白，可能还有其他几十种含量较低的基质蛋白。虽然 肾小球基底膜由足细胞和肾小球内皮细胞共同合成，仅由足细胞合成。 形成主要的IV型胶原，它由3、4和5链组成，它们组装成 形成一种分泌的异源三聚体。影响基底膜IV型胶原成分的突变导致Alport 综合症，导致终末期肾病(ESKD)以及听力和眼睛缺陷。这个 据估计，阿尔波特综合症的患病率为每5,000到10,000名新生儿中就有1名，因此有 世界各地数十万受影响的患者。继发性结构性基底膜异常 IV型胶原的缺陷导致基底膜增厚和分裂，最终导致足细胞足突 肾小球硬化、肾小管间质纤维化。直到最近，还没有治疗方法。 治疗阿尔波特综合征。然而，对小鼠和狗的研究表明，抑制血管紧张素转换酶会减缓肾脏的速度 疾病进展到ESKD。这些动物研究已经在人类Alport综合征中得到验证 血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体阻滞剂的患者现在被认为是 关心。尽管这一治疗突破推迟了ESKD，但它不是治愈的方法；仍然需要新的 有针对性的治疗。该提案的目标是使用创新的、最先进的技术，包括 尝试恢复Alport GBM的小分子、遗传和蛋白质生物化学方法 变成某种正常的成分或通过去除致病成分改变其成分。 在任何一种情况下，人们的预期是，改善GBM的构成至少会使GBM部分正常化 结构和功能。再加上肾素-血管紧张素系统阻断作为护理的标准，这些 治疗应该大大延迟ESKD的时间，并对患者有利。

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.