Podocyte lncRNAs – a novel player in focal-segmental glomerulosclerosis

足细胞lncRNAs——局灶节段性肾小球硬化症的新参与者

• 批准号: 398508019
• 负责人: Professor Dr. Christoph Dieterich
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/398508019?language=en
• 关键词: Podocyte; lncRNAs; novel; player; focal

Non-coding RNAs play an important role both in cellular biology and physiology of numerous tissues and have been linked to several renal pathologies. Large-scale datasets generated by novel sequencing technologies have shown that the majority of transcripts does indeed not possess any coding potential. Among these non-coding transcripts, long non-coding RNAs (lncRNAs) have gained increasing attention due to numerous studies underlining their importance in organ development and disease. However, a large gap has remained between the growing knowledge on lncRNA expression and the question how these transcripts impact on organ function and disease and how they act on the molecular level. It is in fact this knowledge which would be crucial for a better understanding of their contribution to human disease as well as their exploitation as potential therapeutic targets. As to the role of lncRNAs in kidney disease in general only very little is known; regarding podocyte cell biology and associated diseases such as FSGS we lack virtually any insight at all. As a consequence, the emerging field of lncRNAs bears a great potential for identifying novel diagnostic and therapeutic targets by unraveling associated regulatory processes and their impact on renal pathologies. To reach this goal, we have established a bioinformatic pipeline (CALINCA) which allows for the automated identification of lncRNAs that are podocyte-specific, conserved in evolution and dysregulated in FSGS models. Based on these analyses, we have selected several lncRNAs as promising candidates in the pathogenesis of FSGS and have both created novel knockout mouse lines as well as identified optimal cell culture models for these genes. Here, we propose to unravel the role of these lncRNAs in the pathophysiology of FSGS by (1) examining their molecular function in cell culture and murine kidney tissue, (2) characterizing their impact on the pathogenesis and severity of FSGS in mouse models, and (3) evaluating lncRNA expression patterns and localization as a diagnostic marker in patient samples.

非编码RNA在许多组织的细胞生物学和生理学中起重要作用，并且与几种肾脏病理学有关。新测序技术产生的大规模数据集表明，大多数转录本确实不具有任何编码潜力。在这些非编码转录物中，长链非编码RNA（lncRNA）由于许多研究强调其在器官发育和疾病中的重要性而获得越来越多的关注。然而，在lncRNA表达的知识不断增长和这些转录本如何影响器官功能和疾病以及它们如何在分子水平上起作用的问题之间仍然存在很大的差距。事实上，这一知识对于更好地理解它们对人类疾病的贡献以及它们作为潜在治疗靶点的利用至关重要。至于lncRNA在肾脏疾病中的作用，一般来说知之甚少;关于足细胞生物学和相关疾病（例如FSGS），我们几乎缺乏任何见解。因此，lncRNA的新兴领域具有通过解开相关的调节过程及其对肾脏病理的影响来鉴定新的诊断和治疗靶点的巨大潜力。为了实现这一目标，我们建立了一个生物信息学管道（CALINCA），它允许自动识别在FSGS模型中具有足细胞特异性、进化保守性和失调性的lncRNA。基于这些分析，我们选择了几种lncRNA作为FSGS发病机制中有希望的候选者，并创建了新的敲除小鼠品系，并确定了这些基因的最佳细胞培养模型。在这里，我们建议解开这些lncRNA在FSGS的病理生理学中的作用，通过（1）检查它们在细胞培养和小鼠肾组织中的分子功能，（2）表征它们对小鼠模型中FSGS的发病机制和严重程度的影响，和（3）评估lncRNA表达模式和定位作为患者样本中的诊断标志物。