Characterisation of a novel Joubert Syndrome (JS) model: dissecting genotype/phenotype heterogeneity in human disease towards personalised medicine.

关键词：新的治疗策略;弹性，修复和再生，慢性病的机制摘要：囊性肾病占10%的40,000名英国患者需要肾脏替代治疗（透析和移植）。囊性肾病是一组称为“纤毛病”的疾病的一部分，其导致患者中囊性肾病、视网膜变性和脑异常的各种组合。目前没有针对这些病症的疾病修饰治疗。该项目的重点是睫状体病Joubert综合征（JS），其中患者表现为小脑发育不全，视网膜变性（RD），通常患有早发性囊性肾病（肾单位萎缩，NPHP）。JS患者之间存在临床和遗传异质性，这是unexplained.We以前已经描述了一种新的小鼠模型JS（使用Cep 290基因陷阱），更忠实地重演人类的条件比任何其他小鼠，并显示异常刺猬（Hh）信号的基础NPHP的发病。用Hedgehog信号通路的化学激动剂治疗这些小鼠的初级肾集合管细胞挽救了突变的影响，表明突变的影响可以逆转，并且Hh信号通路可以被操纵用于治疗目的。在这个项目中，我们将通过比较2个疾病基因来确定导致疾病异质性的相似性/差异性，从而考虑不同基因突变对JS的贡献。我们将使用已建立的JS模型（CEP 290基因）和新的JS模型（CEP 164基因）（导致更严重的JS形式）。我们的目标是了解不同基因的突变如何导致相同的综合征。通过这种方式，我们将确定潜在的“纤毛病变”的共同特点，一般可以利用开发新的，广泛的治疗干预的一系列不同的综合征的这种类型。

Keywords:new treatment strategies; mechanisms of resilience, repair and regeneration, chronic diseaseAbstract:Cystic kidney disease accounts for 10% of the 40,000 UK patients requiring renal replacement therapy (dialysis and transplantation). Cystic kidney disease is part of a group of disorders referred to as the "ciliopathies" that cause various combinations of cystic kidney disease, retinal degeneration and brain abnormalities in patients. There are no current disease modifying treatments for these conditions. This project focuses on the ciliopathy Joubert Syndrome (JS), in which patients present with cerebellar aplasia, retinal degeneration (RD), and typically suffer early onset cystic kidney disease (nephronophthisis, NPHP). There is clinical and genetic heterogeneity amongst patients with JS which is unexplained.We have previously described a novel mouse model of JS (using a Cep290 gene trap) that more faithfully recapitulates the human condition than any other mouse and shows that abnormal Hedgehog (Hh) signalling underlies the onset of NPHP. Treatment of primary renal collecting duct cells from these mice with chemical agonists of the Hedgehog signalling pathway rescues the effects of the mutation, indicating that the effects of the mutation can be reversed and that the Hh signalling pathway may be manipulated for therapeutic purposes. In this project we will consider the contribution of mutations in different genes underlying JS by comparing 2 disease genes to identify the similarities/differences that lead to disease heterogeneity. We will use an established JS model (CEP290 gene), and a novel JS model (CEP164 gene) (causing a more severe form of JS). We aim to understand how mutations in different genes cause the same syndrome. In this way we will identify common features underlying "ciliopathies" in general that may be exploited to develop new, broad-range therapeutic interventions for a range of different syndromes of this type.