Characterisation of a novel Joubert Syndrome (JS) model to accelerate personalised medicine: from patient to a kidney-in-a-dish via iPS cells.

这个博士项目提供人类疾病遗传学的全面培训，包括人类疾病建模、生物信息学和最新的细胞和分子技术，由一个处于纤毛疾病研究前沿的多学科团队提供，将从根本上增加我们对纤毛疾病的理解，同时提供专门为“基因组时代”量身定做的培训。纽卡斯尔走在了基因组医学最新进展的前沿，例如，作为基因组学英格兰100,000基因组计划的一部分，纽卡斯尔提供了第一个基因诊断(http://www.genomicsengland.co.uk/first-patients-diagnosed-through-the-100000-genomes-project/).The术语纤毛病涵盖了一系列疾病，其特征是囊性肾脏疾病、视网膜退化和患者的大脑异常的各种组合，所有这些都是由影响初级纤毛的突变引起的。在需要透析/移植的40,000名英国患者中，囊性肾病占10%，目前还没有针对这些疾病的治疗方法。这种典型的纤毛病变被称为Joubert综合征(JS)，主要由John Sayer(https://www.ncbi.nlm.nih.gov/pubmed/16682973).教授发现的CEP290基因突变引起塞耶教授和迈尔斯博士创建了一个JS模型，携带与在患者中发现的类似的CEP290突变，并证明该模型真实地概括了人类的情况，比任何其他模型(https://www.ncbi.nlm.nih.gov/pubmed/24946806).更接近对这一模型的分析发现，在肾脏内的Hedgehog信号通路中存在以前未被发现的异常。用刺激Hedgehog信号通路的药物治疗从模型中分离出来的肾细胞，更重要的是，用刺激Hedgehog信号通路的药物治疗JS患者，这些细胞在体外可以恢复正常功能。这表明来自患者的病变肾细胞并不是永久残疾的，我们的模型系统提供了一种确定潜在治疗方法的方法。(http://www.thejournal.co.uk/news/health/newcastle-university-scientists-made-first-7438749).然而，JS患者表现出广泛的症状，例如，i)某一特定基因的突变可导致几种不同临床表型中的任何一种，以及ii)不同基因的突变可导致相同的表型。因此，仅知道突变并不能准确预测患者将患上的疾病类型。这种基因型/表型的异质性使了解疾病的原因、作出准确的诊断和开发特定的治疗方法的努力复杂化。在这个项目中，一个新的JS模型将被表征，基于Arl3基因。最近在我们临床的患者中发现，Ar13突变破坏了与CEP290不同的初级纤毛部分，但导致了相同的疾病。通过比较这两种模型，并与人类基因组数据进行交叉参考，将揭示患者之间存在异质性的机制。了解纤毛疾病的基因型/表型异质性自然会导致在诊断、预后和针对特定的、基因定义的患者群体量身定做特定治疗方面的精确、个性化的医学方法。

Providing a comprehensive training in human disease genetics, encompassing human disease modelling, bioinformatics and state-of-the-art cellular and molecular techniques, delivered by a multidisciplinary team at the forefront of ciliopathy research, this PhD project will fundamentally increase our understanding of ciliopathies, whilst providing training specifically tailored to the "genomic era". Newcastle is at the forefront of recent advances in genomic medicine, for example, delivering the first genetic diagnosis as part of the Genomics England 100,000 genomes project (http://www.genomicsengland.co.uk/first-patients-diagnosed-through-the-100000-genomes-project/).The term ciliopathy covers a wide range of disorders characterised by various combinations of cystic kidney disease, retinal degeneration and brain abnormalities in patients, all arising from mutations affecting the primary cilium. Cystic kidney disease accounts for 10% of the 40,000 UK patients requiring dialysis/transplantation and there are currently no disease-modifying treatments for these conditions.The archetypal ciliopathy is known as Joubert Syndrome (JS) which is predominantly caused by mutations in the CEP290 gene, discovered by Prof John Sayer (https://www.ncbi.nlm.nih.gov/pubmed/16682973). Prof Sayer and Dr Miles created a model of JS, carrying a Cep290 mutation analogous to that found in patients and demonstrated that this model faithfully recapitulates the human condition, more closely than any other model (https://www.ncbi.nlm.nih.gov/pubmed/24946806). Analysis of this model identified a previously unrecognized abnormality in the Hedgehog signalling pathway within the kidney. Treatment of kidney cells isolated from both the model, and more significantly, from JS patients with drugs that stimulate the Hedgehog signalling pathway restores normal function to these cells ex vivo. This indicates that diseased kidney cells from patients are not permanently disabled and that our model systems provide a means to identify potential treatments. (http://www.thejournal.co.uk/news/health/newcastle-university-scientists-made-first-7438749). However, JS patients show a wide range of symptoms, such that i) mutations in one particular gene can cause any one of several different clinical phenotypes and ii) mutations in different genes can cause the same phenotype. Thus, knowing the mutation alone does not accurately predict the type of disease a patient will develop. This genotype/phenotype heterogeneity complicates efforts to understand the cause of the disease, make accurate diagnoses, and develop specific treatments. In this project a novel model of JS will be characterised, based upon the Arl3 gene. Recently discovered in patients in our clinic, Arl3 mutations disrupt a different part of the primary cilium than Cep290, yet cause the same disease. By comparing the two models and cross-referencing with human genomic data, the mechanisms underlying heterogeneity amongst patients will be revealed. Understanding the genotype/phenotype heterogeneity of ciliopathies naturally leads to precision, personalised medicine approaches in terms of diagnosis, prognosis and tailoring specific treatments to specific, genetically defined, groups of patients.