Imperial College London, Alexander Fleming Building, London SW7 2AZ, UK.
King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London SE1 1UL, UK.
Int J Mol Sci. 2018 May 14;19(5):1461. doi: 10.3390/ijms19051461.
Spinal cord injury (SCI) causes irreversible tissue damage and severe loss of neurological function. Currently, there are no approved treatments and very few therapeutic targets are under investigation. Here, we combined 4 high-throughput transcriptomics and proteomics datasets, 7 days and 8 weeks following clinically-relevant rat SCI to identify proteins with persistent differential expression post-injury. Out of thousands of differentially regulated entities our combined analysis identified 40 significantly upregulated versus 48 significantly downregulated molecules, which were persistently altered at the mRNA and protein level, 7 days and 8 weeks post-SCI. Bioinformatics analysis was then utilized to identify currently available drugs with activity against the filtered molecules and to isolate proteins with known or unknown function in SCI. Our findings revealed multiple overlooked therapeutic candidates with important bioactivity and established druggability but with unknown expression and function in SCI including the upregulated purine nucleoside phosphorylase (PNP), cathepsins A, H, Z (CTSA, CTSH, CTSZ) and proteasome protease PSMB10, as well as the downregulated ATP citrate lyase (ACLY), malic enzyme (ME1) and sodium-potassium ATPase (ATP1A3), amongst others. This work reveals previously unappreciated therapeutic candidates for SCI and available drugs, thus providing a valuable resource for further studies and potential repurposing of existing therapeutics for SCI.
脊髓损伤（SCI）会导致不可逆转的组织损伤和严重的神经功能丧失。目前，尚无批准的治疗方法，只有少数治疗靶点正在研究中。在这里，我们结合了 4 个高通量转录组学和蛋白质组学数据集，在临床相关的大鼠 SCI 后 7 天和 8 周，鉴定出损伤后具有持续差异表达的蛋白质。在数千个差异调节实体中，我们的综合分析确定了 40 个明显上调和 48 个明显下调的分子，这些分子在损伤后 7 天和 8 周在 mRNA 和蛋白质水平上持续改变。然后利用生物信息学分析来识别针对筛选分子具有活性的现有药物，并分离在 SCI 中具有已知或未知功能的蛋白质。我们的研究结果揭示了多个被忽视的治疗候选物，这些候选物具有重要的生物活性和可成药性，但在 SCI 中表达和功能未知，包括上调的嘌呤核苷磷酸化酶（PNP）、组织蛋白酶 A、H、Z（CTSA、CTSH、CTSZ）和蛋白酶体蛋白酶 PSMB10，以及下调的三磷酸腺苷柠檬酸裂解酶（ACLY）、苹果酸酶（ME1）和钠钾三磷酸腺苷酶（ATP1A3）等。这项工作揭示了 SCI 的以前未被重视的治疗候选物和现有药物，为进一步研究和潜在重新利用现有的 SCI 治疗方法提供了有价值的资源。
