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Pathophysiology
Workpackages
- WP 3-1 Developmental defects in glomerulosclerosis
- WP 3-2 Ion Transport and electrolyte disorders
- WP 3-3 Endocytosis and nephrotoxicity
- WP 3-4 Small vessel inflamtion
Coordinators: Olivier Devuyst (3-2, 3-3) Pierre Verroust (3-1, 3-4)
Partners: Thomas Willnow, Friedrich Luft, Dominik Müller, Thomas Jentsch,
Andreas Schedl, Erik I. Christensen, Pierre Courtoy, Jakub Gburek, Matthias Kretzler, Jürg Biber, ReceptIcon,
Corrine Antignac
Specific objectives in Pathophsiology (Topic 3)
- establish new mouse and rat models with genetic alterations in key renal genes (transcription factors, ion channels,
transporters, endocytic receptors
- study regulatory networks in (i) cell differentiation, (ii) cellular transport and (iii) cell injury and repair
- identify new targets for therapeutic intervention in (i) glomerulosclerosis,
(ii) electrolyte and blood pressure disorders, (iii) nephrotoxicity and (iv) renal inflammatory disease
Rat and mouse models with perturbations in key renal genes will be established
using knockout and transgene technologies. Focus will be on
genes associated with human renal disease. Sophisticated methods
for characterzation of renal
(dys)function in laboratory animals including morphological
and pathophysiological tests, expression profiling and imaging
will be applied to define disease processes and to uncover novel
regulatory networks in renal (patho)physiology. Studies will
be extended
to nephron
segment-specific cell lines derived from these models. Repositories
for animal models and cell lines
will be established. A comprehensive list of drug targets in
renal pathologies will be compiled.
WP 3-1 Developmental defects and glomerulosclerosis (Partners 3a, 3b, 16)
Specific objectives: Transcrption factors
Wt1 and Pax2, as well as signaling molecules of the Wnt family
play central roles in renal development. Understanding such pathways
is essential since mutations in these genes are involved in tumorigenesis
(Wt1),
developmental
renal disorders (Pax2), and abnormalities in these pathways cause
glomerulosclerosis (Wt1, Pax2). We will define pathopysiological
mechanisms through Wt1, Pax2, and Wnt11 that cause abnormalities
in renal development
and glomeular function in mouse models and in humans.
Specific tasks:
- Task 3-1-1 Wnt11 in renal development
- Task 3-1-2 Wt1 and Pax2 in glomeular disease
WP 3-2 Ion transport and electrolyte disorders (Partners 1, 10, 13)
Specific objectives: Many vital functions depend on proper handling of ions by tubular cells of the kidney. A
number of ion transporters have been identified in renal cells, and their importance demostrated by associtation with human disease. However, the
complex networks involved in their regulation remain unclear. This WP seeks to elucidate protein networks involved in regulation of renal, ion,
phosphate and acid-base transport and in electrolyte disorders using mouse models.
Specific tasks:
- Task 3-2-1 Barttin, a beta-subunit of ClC-K channels
- Task 3-2-2 Cellular sorting of renal ion channels
- Task 3-2-3 Tight junction proteins in paracellular ion transport
- Task 3-2-4 scaffold proteins in phosphate and acid-base transport
WP 3-3 Endocytosis and nephrotoxicity (Partners 1, 3c, 5, 13, 14, 18)
specific objectives: the proximal convoluted
tubules (PCT) are responsible for endocytic uptake of filtered
plasma proteins and resorption deficiencies result in proteinuria, a prominent
feature in
renal disease. Endocytosis not only is essential for retrieval
of metabolites from the primary urine, but also causally involved
in pathological events whereby (i) proteinuria leads to renal
injury and (ii) therapeutic drugs are concentrated by the kidney causing
nephrotoxicity.
We will analyse endocytic processes in PCT and identify targets
to prevent renal injury
through proteinuria and therapeutic drugs.
Specific tasks:
- Task 3-3-1 Endocytic receptor networks
- Task 3-3-2 Mechanisms of endocytosis
- Task 3-3-3 Drug targets in nephrotoxicity
Wp 3-4 Small vessel inflammation and repair (Partners 1, 3c)
Specific objectives: Inflammation of small
vessesls (vasculitis) is a major cause of end stage renal disease.
It may originate from autoimmune mechanisms associated with anti-neutrophil
cytoplasmic
autoantibodies (ANCA), but it is also encountered with severe
hypertension and, although not considered an immune disease,
it involves perturbed T and B cell function. Small vessels in
both conditions feature inflammatory infiltrate, fibrinoid necrosis, and
thrombosis. Our
aim is to use rodent models and pharmacological inhibitors to
elucidate signaling networks that regulate the process of vessel inflammation
and
repair in two paradigms selected for their clinical relevance:
ANCA vasculitis and angiotensin
II-mediated vasculopathy.
Specific tasks:
- Task 3-4-1 ANCA-associated vasculitis
- Task 3-4-2 Hypertension-induced renal inflammation
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