Muckova Petra, Wendler Sindy, Rubel Diana, Büchler Rita, Alert Mandy, Gross Oliver, Rhode Heidrun
Institute of Biochemistry I, University Hospital Jena , Nonnenplan 2-4, 07740 Jena, Germany.
Clinic of Neurology, University Hospital Jena , Erlanger Allee 101, 07740 Jena, Germany.
J Proteome Res. 2015 Dec 4;14(12):5202-14. doi: 10.1021/acs.jproteome.5b00814. Epub 2015 Nov 3.
The efficiency of the inhibition of the angiotensin converting enzyme, the most widely used therapy for the Alport syndrome, depends on the onset of the therapy-the earlier the better. Hence, early progressive biomarkers are urgently required to allow for preclinical diagnosis, an early start of possible therapy as well as the monitoring of this therapy. In the present study, an improved comprehensive and precise proteomic approach has been applied to the serum of juvenile Alport-mice, nontreated and treated, and wild-type controls of various ages to search for biomarkers. With a total of 2542 stringently altered proteins, the serum composition clearly shows a dependency on age, that is, stage, and therapy. Initially, the serum constituents indicate an enhanced extracellular matrix remodeling, cell damage, and the production of particular acute phase proteins. A panel of 15 potential biomarker candidates has been identified. In later stages, renal filtration failure and systemic acute phase reaction determine the composition of the serum; an effect that is well-known for manifested human Alport syndrome. With a small number of mouse urine samples, for example, the proteomic results for gelsolin could be verified using ELISA. Once verified in man, these early biomarkers would allow for a sensitive and specific diagnosis of the Alport syndrome in children as well as facilitate the monitoring of a possible therapy.
血管紧张素转换酶抑制疗法是治疗奥尔波特综合征最广泛使用的方法，其疗效取决于治疗开始的时间——越早越好。因此，迫切需要早期进展性生物标志物，以便进行临床前诊断、尽早开始可能的治疗以及监测该治疗。在本研究中，一种改进的全面且精确的蛋白质组学方法已应用于幼年奥尔波特小鼠、未经治疗和经治疗的小鼠以及不同年龄的野生型对照小鼠的血清，以寻找生物标志物。共有2542种蛋白质发生了显著变化，血清成分明显显示出对年龄（即阶段）和治疗的依赖性。最初，血清成分表明细胞外基质重塑增强、细胞损伤以及特定急性期蛋白的产生。已鉴定出一组15种潜在的生物标志物候选物。在后期阶段，肾滤过功能衰竭和全身急性期反应决定了血清成分；这一效应在已确诊的人类奥尔波特综合征中是众所周知的。例如，通过少量小鼠尿液样本，凝溶胶蛋白的蛋白质组学结果可以用酶联免疫吸附测定法进行验证。一旦在人体中得到验证，这些早期生物标志物将有助于对儿童奥尔波特综合征进行灵敏且特异的诊断，并便于监测可能的治疗。
