An investigation into the genetic and functional basis of proteinuric kidney disease

慢性肾脏疾病影响了英国13%的人口，有5.9万名英国患者要么需要透析，要么需要依靠肾脏移植来治疗肾衰竭。全世界有190万患者接受了这些肾脏替代疗法，还有更多的人无法获得这些昂贵而有限的资源。肾脏疾病通常与蛋白质异常渗入尿液有关，例如在罕见的遗传性疾病和糖尿病中，糖尿病是全球肾衰竭的主要原因。这种蛋白质泄漏是由于过滤屏障的失败，通过过滤屏障，健康的肾脏扮演着选择性筛子的角色，过滤废物和多余的水，但保留血液中的重要蛋白质。被称为足细胞的独特细胞是这一障碍的关键组成部分，但由于它们不能复制，而且很难从基因上改变，足细胞给研究带来了特殊的挑战。为了开发更有效、更安全的治疗方法，我们需要更多地了解足细胞和滤过屏障的损害如何导致蛋白质泄漏和疾病。患者的基因组测序计划已经开始揭示许多与严重的蛋白质泄漏有关的基因。然而，由于人类彼此之间携带着许多基因差异，因此很难从候选基因名单中准确确定到底是哪种基因导致了这种疾病。该项目的目的是通过应用最新的技术进步来精确和高效地操纵基因来解决这个问题。这些方法将被用于开发和研究携带患者突变的肾脏疾病模型。通过测量基因破坏对细胞和生物体的影响，我们将识别新的疾病基因，直接导致更多罕见肾脏疾病患者的基因诊断。这种基因诊断可以通过量化不同个体的风险并帮助规划来帮助患者和家人，即使它不会立即改变治疗。这个项目产生的人类基因变异模型将导致在细胞和组织水平上更详细地研究肾脏生物学。该项目的另一个目标是探索将基因与疾病联系起来的方法，使用测序技术来测量“开启”的基因的图景。这些技术将在单个细胞和肾脏组织水平上收集和比较信息。在未来，这种方法可能会在人体组织中得到临床应用，比如肾脏活检样本。从长远来看，更好的研究遗传差异的工具，以及更好地了解突变对途径和细胞系统的影响，将为治疗肾脏疾病提供新的目标，改善个人结果，并减轻慢性肾脏疾病的健康和经济负担。

Chronic kidney disease affects 13% of the UK population, with 59,000 UK patients either on dialysis or dependent on a kidney transplant for the treatment of kidney failure. Worldwide 1.9 million patients receive these kidney replacement therapies, with many more unable to access these expensive and limited resources. Kidney disease is often associated with abnormal leak of protein into the urine, for example in rare inherited diseases and in diabetes, the leading cause of kidney failure worldwide. This protein leak is due to failure of the filtration barrier, by which healthy kidneys act as selective sieves, filtering waste products and excess water, but keeping important proteins in the blood. Unique cells called podocytes are key component of this barrier, but because they do not replicate and are difficult to alter genetically, podocytes present specific challenges for research. In order to develop more effective, safer treatments, we need to understand more about how damage to podocytes and the filtration barrier leads to protein leak and disease. Genome sequencing projects in patients have begun to reveal many genes associated with a severe protein leak. However, because humans carry many genetic differences from each other it can be difficult to pinpoint which gene from a shortlist of candidates actually causes the disease. The aim of the project is to address this problem, by applying recent advances in techniques to manipulate genes precisely and efficiently. These methods will be used to develop and study models of kidney disease carrying patient mutations. By measuring the effects of gene disruption on cells and organisms, we will identify new disease genes, leading directly to a genetic diagnosis for more patients with rare kidney diseases. This genetic diagnosis can help patients and families, even if it does not immediately change treatment, by quantifying risk in different individuals and helping with planning.The models of human gene variation produced in this project will lead to more detailed study of kidney biology at the level of cells and tissues. One further aim of the project is to explore ways to connect genes to disease, using sequencing techniques to measure the landscape of 'switched on' genes. These techniques will gather and compare information at the level of individual cells and kidney tissues. In the future this approach may have clinical applications in human tissue such as kidney biopsy samples. In the long term, better tools for investigating genetic differences and greater understanding of the effects of mutations on pathways and cellular systems will provide new targets for treating kidney disease, improve outcomes for individuals and reduce the health and economic burdens of chronic kidney disease.