GEN-AU
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BIOINFORMATICS INTEGRATION NETWORK (BIN III)
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The flood of data arising from genomic-scale studies
performed within the GEN-AU research program poses significant challenges. During
the first phase of the GEN-AU program, as part of a strategy to turn these challenges
into opportunities and chances, we assembled a consortium of research partners
within the Bioinformatics Integration Network (BIN) and established a computational
laboratory for the integration of bioinformatics solutions. During this phase we
established three thematic nodes with complementary expertise: (i) bioinformatics
services and database integration, (ii) sequence annotation and (iii) structural
genomics. During the second funding period we expanded and improved the backbone
for bioinformatics services and broadened the scope of the thematic nodes by
establishing proteomics informatics and evolutionary sequence analysis.
The continuous development and application of novel technologies for generating
high-throughput data requires the parallel development of computational methods
and tools to manage, store, and analyze the data. The BIN III consortium therefore
plans to maintain and enrich the computational laboratory and strengthen
interactions with the experimental partners during the third funding period.
The goal of the BIN III project is to provide bioinformatics services and use computational methods to address biological questions arising from the GEN-AU projects. Specifically, our aims are:
 To provide an environment for bioinformatics services and continuously improve bioinformatics resources for the large-scale projects within the Austrian genome research program GEN-AU. The bioinformatics services developed and installed during BIN I and BIN II will be maintained and improved and the available databases, services and systems will be adapted to emerging software technology and new hardware requirements.
To develop novel computational methods for the analysis of biomolecular data. All individual components will direct major research activities with the aim of developing computational methods for the analysis of biomolecular data and validation of the methods in a biological context. We will focus on two specific areas: gene regulation and the modeling of molecular networks.
To validate the developed methods and address biological questions posed by the GEN-AU projects. In collaboration with the experimental partners from other GEN-AU projects we will apply the computational methods developed in the preceding aim to address biological questions and/or validate the methods. Experiments will be designed and performed in close collaboration with the computational biologists to generate the necessary data.
To promote the development of bioinformatics and computational biology in Austria by providing education and training at the undergraduate and graduate levels. We will continue the PhD program with special emphasis on the education of core personnel for bioinformatics. The network will furthermore continue to organize workshops for biologists in the GEN-AU projects, arrange a series of lectures featuring distinguished bioinformatics speakers and offer additional working places for guest scientists at the network nodes.
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GENOMICS OF LIPID ASSOCIATED DISORDERS (GOLD III)
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Comparative transcriptomics of models of lipid-associated disorders
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Lipids are fundamental to all living species.
Among other functions, they constitute the matrix of biological membranes,
comprise the permeability barrier in skin, serve as major energy substrates,
and act as hormones and biological signals to control numerous cellular processes
such as gene transcription and growth. To assure sufficient lipid supply under
varying nutritional conditions, special storage strategies for lipids have evolved.
Most eukaryotic species accumulate lipids in lipid droplets (LD) within specialized
cells. In vertebrates, most lipids are stored in adipose tissue, however, smaller
amounts of LD are also found in essentially all other cell types of the body. A
complex functional network of enumerable enzymes, structural proteins, and
regulatory factors accounts for functional lipid homeostasis and a balanced
metabolism.
Dysregulation or dysfunction
of these processes causes highly prevalent metabolic diseases such as obesity,
atherosclerosis, and type-2 diabetes.
The GOLD III project aims to discover genes, gene products, and metabolites
required for the generation, structural integrity, and catabolism of LD.
Elucidation of the effectors’ structures, functions, and regulation will reveal
currently unknown mechanisms and pathways that control lipid and energy homeostasis.
Epidemiological studies will disclose the medical relevance of our discoveries.
In summary, these results will provide important insights into the pathogenesis
of metabolic diseases and provide potential drug targets for their treatment.
To achieve these goals, thirteen research teams from six Austrian universities will
constitute the GOLD III consortium. The “GOLD approach” of highly focused research
objectives, an excellent scientific track record, and broad methodological expertise
has been remarkably successful in the past and will ensure important discoveries with
potential for economic exploitation also during the final period of GEN-AU.
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NON-PROTEIN CODING RNAS: FROM IDENTIFICATION TO FUNCTIONAL CHARACTERIZATION (ncRNA)
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Functional characterization of microRNA-mRNA pairs targeting adipogenesis and obesity (Research Area microRNAs)
(PI: Marcel Scheideler; Email: marcel scheideler@tugraz.at)
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In cells from all organisms studied to date two different
types of RNAs are found: messenger RNAs (mRNAs), which are translated into proteins and
so-called non-protein-coding RNAs (ncRNAs), which are not translated into proteins but
function at the level of the RNA itself. Intriguingly, although only 1.5% of human DNA
constitute protein-coding sequences, recent research has revealed that actually more
than 90% of the genome is transcribed. This coincides with the discovery of several classes
of non-coding, yet functional RNA during the last years, including microRNAs (miRNAs),
regulating a plethora of biological processes and being involved in a variety of diseases.
The therapeutic potential of miRNAs has recently been highlighted by studies in mouse and
non-human primates depicting miRNAs as key molecules for future medicine.
Obesity, one of the most prevalent diseases worldwide, with more than 1.1 billion adults
overweight and 300 million of them clinically obese, and furthermore predisposing to other
common afflictions like type 2 diabetes, atherosclerosis, and osteoporosis, has also been
associated with miRNAs, but only by a few studies so far, with the potential for many more.
Indeed, we could identify several microRNAs with a functional role in human adipogenesis.
Therefore, we aim at the functional characterization of miRNA/target pairs that regulate
adipogenesis and obesity, thereby resulting in novel candidates as potential drug targets
which might contribute to the development of novel, innovative therapeutic opportunities
for the treatment of the global obesity epidemic.
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FWF
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| LIPOTOXICITY: LIPID-INDUCED CELL DYSFUNCTION AND CELL DEATH |
Transcriptional regulation of lipotoxic pathways
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| The goal of the SFB-LIPOTOX is to unify relevant research forces in Graz on
one theme: Lipotoxicity. The research consortium defines lipotoxicity as the
anomalous uptake, generation, and activity of lipid derivatives mediating
adverse, "lipotoxic" effects including dysregulation of metabolic pathways,
cell- and organelle dysfunction, and cell death. To investigate lipotoxicity as
a pathological basis of human disease and to discover molecular processes that
can prevent lipotoxicity, we propose to identify and characterize the molecular
and cellular mechanisms activated by lipotoxic substances. Genomic, proteomic,
and lipidomic technology will be utilized to discover novel lipotoxic pathways.
Mutant mouse and yeast models will be analyzed to elucidate the mechanisms that
cause the production of toxic lipid compounds, lead to cellular dysfunction, and
induce apoptosis or other forms of cell death. It is evident that such a broad
scientific aim requires a conceptual strategy that supersedes the singular focus
of individual research groups, and that ensures effective exchange of ideas,
expertise and resources. The SFB program of the FWF provides the appropriate
framework for a dynamic and interactive research consortium embedded in a number
of related project programs. We expect our findings to contribute to the
identification of valid targets for disease intervention. |
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Specifically, we aim in our subproject to: |
Identify gene sets and pathways associated
with lipotoxicity across tissues and species by comparative computational genomics. In this project we will be
able for the first time to perform comparative analyses of genes and pathways involved in lipotoxicity across
tissues and species. Using data from adipose tissue, muscle, heart, liver, macrophages, and neurons we will be
able to identify gene sets and pathways selectively and commonly expressed in the mouse models of lipotoxicity.
We will then explore the relevance of the identified targets for human disease by comparative analyses of
expression profiles.
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CHRISTIAN DOPPLER LABORATORY
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IDENTIFICATION AND CHARCTERIZATION OF NOVEL GENES AND THEIR PRODUCTS THAT ARE RELEVANT TO METABOLIC DISEASES
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| The principal goal of our
research plan is to link genes to function on a genomic scale in order
to facilitate investigations of physiological and pathophysiological mechanisms
underlying metabolic diseases. Together, researchers at the Institute
for Genomics and Bioinformatics, the company Oridis Biomed and the company
Eccocell have developed a broad-based response to this challenge in which
we will develop a number of reagents, tools, and techniques that will
allow us to provide links between physiologically relevant animal models
of human disease and the genes that are differentially expressed in those
phenotypes. |
| The starting point for our proposed studies are mouse phenotypes that
are relevant to liver diseases and obesity, and corresponding human disease
tissues. Expression profiling will be performed using murine cDNA microarrays
constructed in our laboratory and human disease-specific cDNA microarrays
generated by Oridis Biomed as well as genome-sized human microarrays that
will be produced. Expression data will be analyzed using: a) large-scale
functional prediction on gene sets selected by expression criteria from
cDNA microarray data, and b) large-scale comparative analyses of the human
and mouse transcripts. Finally, to characterize the biochemical and cellular
function of the target proteins, protein expression patterns in normal
and diseased tissues will be examined using tissue microarrays. The combination
of cDNA microarrays, specific mouse models, access to corresponding human
disease tissue and the resulting expression profile comparisons makes
our approach unique and innovative. |
| The research plan we outline represents a departure from traditional hypothesis-driven
research. Rather, it is a model of discovery-driven research in which our
assays, both of phenotype and of expression, will provide the data and resources
to facilitate the formulation and testing of well-defined hypotheses. In
order to make the most judicious use of our resources, we will coordinate
our efforts with the participants from the Austrian genome project GEN-AU
GOLD (Genomics Of Lipid-associated Disorders). |
Overall Specific Aims:
The mission of our proposal is to identify subsets of genes that are particularly
relevant to the biology, diagnosis, management, treatment, and prevention
of metabolic disorders and to prioritize the information for further focused
study. We will achieve this through microarray analysis of patterns of gene
expression in mouse models of liver disorders and obesity, corresponding
human disease tissue, computational analyses of the data, and functional
characterization.
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