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Complex Genetics of Renal Diseases
Workpackages
- WP 4-1 Genetics of Model Systems (I)
- WP 4-2 Genetics of Model Systems (II)
Coordinators: Roger Cox (4-1), Corinne Antignac (4-2)
Partners: Rajesh Thakker, Giuseppe Remuzzi, Nick Hastie, Allan Wright
Specific objectives in Complex genetics (Topic 4)
- establish new models by ENU mutagenesis in zebrafish and mouse
- map modifier QTLs for proteinuria and progressive renal injury in rats
- identify modifiers in diabetic nephropathy in mice
- map QTLs for (i) glomerulosclerosis and (ii) renal stone disease in mouse models
Systematic random ENU mutagenesis approaches in zebrafish and mouse will be applied to generate new models of impaired renal development and
function, which will be further characterized by pathophysiological and positional cloning approaches. established rodent models of diabetic
nephropathy, glomeulsclerosis, proteinuria and renal stone disease will be used to map modifier QTLs that affect disease progressionand to identify
new disease genes by linkage/positional cloning.
WP 4-1 genetics of model systems (I) (Partners 2a, 2b, 15)
Specific objectives: Here we will apply a hgih throughput random ENU (N-ethyl nitrosourea, a powerful random
point mutagen) mutagenesis approach to systematically screen for renal disease genes in zebrafish and mouse at large scale. identified genes will
feed into human studies in WP 4-3 of this topic anf into relevant projects in T2 (Renal development) and T3 (Pathophysiology). New fish and mouse
models will be archived and made available to the scientific community.
Specific tasks:
- Task 4-1-1 Pilot genetic screens in zebrafish
- Task 4-1-2 Blood and urine screen of ENU mutagenized mice
- Task 4-1-3 Mouse allelic series in candidate genes for nephropathy
WP 4-2 Genetics of model systems (II) (Partners 2b, 3b, 8, 15)
Specific objectives: Our main objective is to identify novel genes that play a tole in renal development and
pathology through the use of model systems. In contrast to a systematic approach in WP 4-1, the approach in WP 4-2 will be objective -driven and focus
on established pathophysiological models in rats and mice to identify QTLs that affect onset and progression of diesease processes.
Specific tasks:
- Task 4-2-1 Mapping and cloning kidney stone ENU mutant mice
- Task 4-2-2 Candidate genes for proteinuria and progressive renal injury in rats
- Task 4-2-3 Modifiers of focal segmental glomerulosclerosis in podocin mutant mice
- Task 4-2-4 elucidating disease progression in diabetic nephropathy in the mouse
