Projektbeschreibung
Genbasierter Ansatz gegen chronische Nierenerkrankung
Die chronische Nierenerkrankung (CKD, chronic kidney disease) ist eine komplexe, heterogene Erkrankung, bei der nach und nach Nierenversagen eintritt. Weltweit sind Millionen Menschen betroffen. Verschiedene Studien belegen die Erblichkeit von CKD durch die Bestimmung der entsprechenden Genloci. Doch diese Gene erklären nicht alle Fälle der Anfälligkeit für CKD. Die Mission des EU-finanzierten Projekts GeneCKD ist es, die genetische Grundlage der chronischen Nierenerkrankung zu erkennen und die kausalen Zusammenhänge der Erkrankung zu verstehen. Der Schwerpunkt liegt dabei auf dem nierenspezifischen Protein Uromodulin und dem Entwurf neuer Interventionen zur Bekämpfung der toxischen Auswirkungen durch eine abweichende Uromodulinexpression. Die Ergebnisse werden die Früherkennung erleichtern und neue genbasierte Behandlungswege für diese Erkrankung eröffnen.
Ziel
Chronic Kidney Disease (CKD) is a public health challenge affecting millions globally. Patients have increased risks of mortality, morbidity, and progression to end-stage kidney disease (ESKD). CKD is often clinically silent, disease mechanisms are unclear and targeted therapies are unavailable. Recent studies support considerable contributions of underappreciated monogenic aetiologies in adults with CKD, suggesting that most inherited kidney diseases remain undiagnosed, untreated and poorly understood. Our overarching objective is to unravel the genetic basis of CKD towards early diagnosis and gene-based therapy. We therefore established the Israeli ESKD genetic cohort and already recruited clinical data and samples from 2,000 participants with ESKD. Our main objectives are: 1) to unravel known and novel CKD genes by interrogating high-risk groups for genetic CKD using next generation sequencing on a population level; 2) to study novel monogenic CKD disease mechanisms by using patient-derived kidney organoids and mutation-specific mouse models. Specifically, we will study a newly identified WDR19 mutation leading to many adult onset-ESKD cases in the Israeli Arab-Druze population; and 3) to develop gene-based targeted therapies for CKD. We will focus initially on monogenic CKD secondary to gain-of-toxic-function mutations in UMOD (encoding uromodulin, a kidney-specific protein). This relatively frequent adult CKD aetiology accounts for 0.5-2% of CKD cases worldwide. Altered uromodulin?s toxic effect is suitable for novel RNA-based therapies. Gene silencing of uromodulin with antisense oligonucleotides will be performed and studied, using a patient-derived in vitro model as well as a Umod mouse model. This project will improve CKD classification and clinical management, reveal disease mechanisms as well as novel treatments. In a broader perspective, this project will set the stage for future clinical trials and for other RNA-based gene-specific CKD treatments.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
52621 Ramat Gan
Israel