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Personalised medicine in Joubert syndrome: patient-specific human urine-derived epithelial cells as a disease model and platform for therapeutic devel

朱伯特综合征的个体化医疗：患者特异性人尿源性上皮细胞作为疾病模型和治疗开发平台

基本信息

批准号：
2388058
负责人：
金额：
--
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2388058
关键词：
Personalised medicine Joubert syndrome patient

项目摘要

"Ciliopathies" account for 10% of the 40,000 UK patients requiring dialysis/transplantation. These disorders cause cystic kidney disease, retinal degeneration and brain abnormalities, as typified by Joubert syndrome (JS) but widespread genotype-phenotype heterogeneity poses a challenge for dissecting disease pathobiology. There are currently no disease-modifying treatments for these conditions and the development of treatments will require patient-specific, personalised approaches. The supervisors (https://www.ncl.ac.uk/igm/staff/profile/johnsayer.html#background and https://www.ncl.ac.uk/igm/staff/profile/colinmiles.html#background) have developed a "pipeline" from gene discovery [eg, Nat Genet. 2006 38(6):674; Am J Hum Genet. 2018 103(4):612], through creation of mouse models [eg, Proc Natl Acad Sci USA. 2014 111(27):9893] for identification of therapeutic targets, and back to the patient for testing and validation of potential treatments on kidney cells directly isolated from patients [eg, Hum Mol Genet. 2017 26(23):4657 & Proc Natl Acad Sci 2018]], known as human Urine-derived-Renal-Epithelial-Cells (hURECs)n https://www.chroniclelive.co.uk/news/health/newcastle-university-kidney-research-sayer-15431046. Whilst the supervisors lead the field in research involving hURECs, these cells remain the least understood part of this pipeline and further detailed understanding and development of this platform will be essential for translating our findings to the clinic. Currently studies involving hURECs are limited to those patients within a few hours of the laboratory and there is an urgent need to overcome this limitation, eg, we have patients worldwide (from USA to the Middle East) but at present must send our researchers to where the patients are. Therefore, in parallel, this project will be carried out in collaboration with Atelerix (https://www.atelerix.co.uk/) pioneers in the storage and transport of specialised human cells. The project will involve detailed phenotypic characterisation of hURECs from a panel of JS patients compared with hURECs from healthy volunteers and hURECs that have been engineered (siRNA and/or CRISPR/Cas9) to model specific aspects of disease. In addition to standard immunohistochemistry, a key enabling technology for this project is the Genomics Core Facility underpinned by recent >£1M investments from Newcastle University (https://www.ncl.ac.uk/igm/research/facilities/genomicscf/ ) that will allow us to perform "single cell RNAseq" on hURECs to characterise these cells in unprecedented detail. These data will be overlayed on normal kidney datasets to precisely define the cellular composition of hUREC cultures and subsequently, disease mechanisms will be identified by comparison with data from patient-specific mouse models (ie, mice engineered to carry the identical amino acid change as the patient). This PhD will provide a comprehensive training in state-of-the-art human disease genetics coupled with an industrial perspective on the development of essential technologies, delivered by a multidisciplinary team at the forefront of ciliopathy research.

在英国需要透析/移植的40，000名患者中，“纤毛病”占10%。这些疾病导致囊性肾病、视网膜变性和脑异常，如以Joubert综合征（JS）为代表，但广泛的基因型-表型异质性对解剖疾病病理生物学构成了挑战。目前还没有针对这些疾病的疾病改善治疗方法，治疗方法的开发将需要患者特异性的个性化方法。监管者（https：www.ncl.ac.uk/igm/staff/profile/johnsayer.html#background和https：//www.ncl.ac.uk/igm/staff/profile/colinmiles.html#background）已经开发了一个来自基因发现的“管道”[例如，Nat Genet. 2006 38（6）：674; Am J Genet. 2018 103（4）：612]，通过创建小鼠模型[例如，Proc Natl Acad Sci USA. 2014 111（27）：9893]用于鉴定治疗靶点，并返回患者用于测试和验证对直接从患者分离的肾细胞的潜在治疗[例如，Genet. 2017 26（23）：4657 & Proc Natl Acad Sci 2018]]，称为人尿衍生的肾上皮细胞（hUREC），参见https://www.chroniclelive.co.uk/news/health/newcastle-university-kidney-research-sayer-15431046。虽然主管领导了涉及hUREC的研究领域，但这些细胞仍然是该管道中最不了解的部分，进一步详细了解和开发该平台对于将我们的发现转化为临床至关重要。目前，涉及hUREC的研究仅限于实验室几小时内的患者，迫切需要克服这一限制，例如，我们在世界各地（从美国到中东）都有患者，但目前必须将我们的研究人员派往患者所在地。因此，与此同时，该项目将与Atelerix（https：//www.atelerix.co.uk/）合作，在专门的人类细胞的储存和运输方面开拓者。该项目将涉及来自一组JS患者的hUREC的详细表型表征，与来自健康志愿者的hUREC和已被工程化（siRNA和/或CRISPR/Cas9）以模拟疾病的特定方面的hUREC进行比较。除了标准的免疫组织化学，该项目的一个关键使能技术是由纽卡斯尔大学（https：//www.example.com）最近> 100万英镑的投资支持的基因组学核心设施，这将使我们能够对hUREC进行“单细胞RNAseq”，以前所未有的细节对这些细胞进行测序。www.ncl.ac.uk/igm/research/facilities/genomicscf/这些数据将覆盖在正常肾脏数据集上，以精确定义hUREC培养物的细胞组成，随后，将通过与患者特异性小鼠模型（即，经工程改造携带与患者相同氨基酸变化的小鼠）的数据进行比较来鉴定疾病机制。该博士学位将提供最先进的人类疾病遗传学方面的全面培训，以及对基本技术发展的工业观点，由位于纤毛病研究前沿的多学科团队提供。