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| Summary |
| In Europe, an estimated
4,5 Million people suffer from chronic renal disorders.
The elderly are disproportionately affected, but renal
disease is also a condition that severely affects children.
Diseases of the kidney represent a major cause of morbidity
and mortality in the western world. The death rate in patients
with kidney failure is 20% annually. This disease burden
and its challenge for our societies is the focus of this
proposal.
Elucidation of the complete human DNA
sequence and that of other organism heralds a new era in
biomedical research offering unprecedented opportunities
to understand disease processes and to identify strategies
to improve health.
We will embrace these opportunities
and implement an interdisciplinary research program, the
European Renal Genome Project (EuReGene). It will integrate
European excellence in research relevant to kidney development,
pathophysiology and genetics. Our goal is to discover genes
responsible for kidney development and disease, their proteins
and their actions.
To achieve this goal, we have established
a consortium of leading scientists, clinicians and SME
partners (small and medium sized enterprises), that will
focus on the development of novel technologies and discovery
tools in functional genomics and their application in kidney
research. We will rely on studies that compare the genetic
code of many systems that provide useful models ranging
from zebrafish, to frog, to mice and to rats. Our studies
will be performed at different levels including the gene,
the cell, the organ and the entire organism.
Ultimately, identification of
disease genes will lead to a better understanding of
kidney diseases processes, to improved diagnosis and
to new concepts in therapy. Our program will set an example
for an integrated approach using the genetic information
now available to analyze renal disease-related developments
that may be transferred to other organ systems or diseases
in the future.
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| Global objectives |
| Since the completion of the human and other
genome projects the newly available genetic information offers
unprecedented opportunities for comparative analysis of many
genomes aimed at creating fundamental knowledge about the
genetic basis of human disease. EuReGene will develop functional
genomic tools, methodologies and resources (including animal
models) tailored to the needs of kidney research and apply
them to kidney development and disease, where they are most
needed. Knowledge generated in the program will be available
to the scientific community and to the stakeholders through
freely accessible databases and websites. |
| EuReGene will pursue specific objectives
in four areas that are most relevant to functional genomic
research in human kidney disease: |
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Functional
genomics technologies (Topic 1) |
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Renal development (Topic 2) |
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Pathophysiology (Topic 3) |
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Complex
genetics (Topic 4) |
| The generation of novel tools, methodologies
and resources for genome research (Topic 1) are technological
objectives that apply to and overarch all scientific
objectives in the disease-related projects |
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on Renal development
(Topic 2), Pathophysiology of primary and acquired renal
disorders (Topic 3) and Complex genetics of kidney diseases
(Topic 4) (see figure).
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| Model Systems |
| The usage of animal models is one of the important
methods used within the research consortium. The relevant
organs of the selected species hold a pronounced analogy
to human kidney. Therefore they can be used as models. Even
though a certain simplification is inevitable, the developmental
processes can be determined and compared with human kidney
(disease) development. The effect of new therapeutical measures
needs also to be tested in models before it can be applied
to humans.
Please note that animals are not used lightly in the EuReGene
project. As much as possible, alternative research strategies
are pursued. However, for certain studies the use of animals
remains necessary. Naturally, theses studies all comply
with the strict requirements placed upon us by the animals
ethics committees of the participants.
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| Within EuReGene the following animal models
are used: |
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Zebrafish embryos
have emerged as an attractive model to study kidney
development. Professor Nick Hastie
runs an established fish facility supported by 2 full-time
assistants. His lab has generated reporter strains
to mark specific renal cell types using fluorescence
and
to follow which cells grow into which structures. Within
EuReGene, he generate genetic variants and will perform
screens to identify genes that regulate renal development.
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Xenopus (frog)
is another lower vertebrate model that represents
a simple model of
nephron development
(the basic functional structure of the kidney). Professor
André Brändli has extensive experience
using this model system to study key genes in renal
development
and he runs the largest state-of-the-art Xenopus facility
in Switzerland. Here, we will establish a gene
expression atlas of the developing and the adult kidney. In a
large scale experiment, the activity of all genes that
are
potentially important in the kidney will be determined
at different time points during the development of
the kidney. This will then be compared with the activity
of similar genes in the mouse kidney.
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Mice are
the higher vertebrate model of choice to perform
genetic manipulation and test gene function.
Approximately half the participating groups have experience
in generating mouse models. Here, we will use both
systematic creation of genetic variants and candidate
gene disruption
to explore disease genes. In systemic approaches Professor
Roger Cox will use chemically induced genetic variants
in mice and their sperm to produce models at large
scale. In terms of candidate genes, many partners will
apply gene
inactivation to study loss of gene function; generate
lines to map cell fate during development using fluorescence,
and use tissue-specific overexpression (increased
gene activity) to determine the contribution of genes
to disease
processes in several kidney diseases. Professors Nick
Hastie and Andreas Schedl will develop novel mouse
cell lines and organ cultures as alternative experimental
systems to study kidney development and function.
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Rats offer disease models that sum up many
features of genetic complexity and the disturbed physiology
of kidney processes leading to disease as seen in patients.
Dr. Giuseppe Remuzzi and Professor Friedrich Luft will
use sponteneous rat models of kidney injury leading to
protein loss and transgenic rat models of hypertension
(high blood pressure) induced kidney damage to analyze
candidate genes in common kidney injury processes.
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