Discovery and functional characterization of novel single-gene causes and genetic modifiers in nephronophthisis

肾结核新单基因病因和遗传修饰物的发现和功能表征

• 批准号: 441216213
• 负责人: Dr. Friederike Petzold
• 金额: --
• 依托单位: Klinik und Poliklinik für Endokrinologie, Nephrologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/441216213?language=en
• 关键词: Discovery; functional; characterization; novel; single

Chronic kidney disease (CKD) affects as many as 10-15% of the worldwide population and is increasingly recognized as a significant global health burden. Inherited kidney diseases represent the fifth most common cause of CKD and end-stage renal disease (ESRD). While among adults autosomal-dominant polycystic kidney disease (ADPKD) is the prevailing condition, nephronophthisis (NPH) constitutes the most frequent genetic cause in the first decades of life. NPH is a chronic tubulointerstitial nephropathy characterized by interstitial fibrosis and microcyst formation with a recessive mode of inheritance. NPH can either present as isolated renal disease or as syndromic disease with extra-renal organ involvement. Together with ADPKD, NPH belongs to the spectrum of renal ciliopathies sharing underlying defects in primary cilia-dependent signaling pathways. Although identification of more than 20 NPH causing genes has advanced our understanding, the majority of clinically suspected NPH cases still remain genetically unsolved. The proposed project aims to i) identify novel NPH disease genes using a step-wise strategy based on targeted-gene panel, whole exome, and whole genome sequencing, ii) detect genetic modifiers accounting for interfamilial disease variability in a cohort of syndromic and non-syndromic NPHP1-patients, iii) characterize novel disease mechanisms with regards to ciliary function in cellular and animal NPH-models to test novel pharmaceutical approaches. The work group of Sophie Saunier at the Imagine Institute of Genetic diseases in Paris provides an excellent infrastructure characterized by innovative research methods and profound research experience in the field of ciliopathies to successfully pursue the proposed project.

慢性肾脏疾病(CKD)影响着多达10%-15%的全球人口，并日益被认为是一个重大的全球健康负担。遗传性肾脏疾病是CKD和终末期肾病(ESRD)的第五大常见原因。在成人中，常染色体显性遗传性多囊肾病(ADPKD)是最常见的疾病，而肾单位病(NPH)是生命最初几十年最常见的遗传原因。NPH是一种以间质纤维化和微囊形成为特征的慢性肾小管间质肾病，具有隐性遗传方式。NPH既可以表现为孤立的肾脏疾病，也可以表现为肾外器官受累的综合征疾病。与ADPKD一起，NPH属于肾纤毛疾病的谱系，共享初级纤毛依赖信号通路的潜在缺陷。尽管20多个NPH致病基因的发现促进了我们对NPH的认识，但大多数临床疑似NPH病例仍未从遗传学角度得到解决。该项目的目标是：i)使用基于靶向基因小组、整个外显子组和全基因组测序的逐步策略来识别新的NPH疾病基因；ii)在一组综合征和非综合征NPHP1患者中检测可解释家族间疾病变异性的遗传修饰因素；iii)在细胞和动物NPH模型中表征关于睫状体功能的新的疾病机制，以测试新的药物治疗方法。巴黎基因疾病想象研究所的索菲·索尼耶工作组提供了出色的基础设施，其特点是在纤毛疾病领域具有创新的研究方法和深厚的研究经验，以成功开展拟议的项目。