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GENOMICS AND BIOINFORMATICS GRAZ

© 2011 Institute for Genomics and Bioinformatics · Graz University of Technology · Petersgasse 14, 8010 Graz, Austria Tel +43-316-873-5331 · Fax +43-316-873-5340 · URL http://genome.tugraz.at ·   · Welcome to Graz · Map

EU

DIABAT: RECRUITMENT AND ACTIVATION OF BROWN ADIPOCYTES AS PREVENTIVE AND CURATIVE THERAPY OF TYPE 2 DIABETES Marcel Scheideler, RNA Biology Group

The prevalence of obesity has reached pandemic dimensions. Triggered by the excessive expansion, remodelling and dysfunction of adipose tissue in the obese state, type 2 diabetes and its associated cardio-vascular complications have emerged as the leading causes of death in Western countries, associated with estimated health care costs of more than 30 billion Euros in the European Union per year. Brown adipose tissue (BAT) is currently a worldwide recognized target to combat obesity and diabetes due to the very recent re-discovery of functional BAT in adult humans by several of the members of the DIABAT network (Nedergaard et al., 2007) (van Marken Lichtenbelt et al., 2009) (Virtanen et al., 2009) along with a sharp rise in insight in cellular, genetic, and regulatory mechanisms from animal studies. The overall objective of the DIABAT project is to recruit and re-activate endogenous energy-dissipating BAT as a preventive and/or remedial measure for weight and blood sugar control in obesity-related type 2 diabetes (“diabesity”), thereby halting or preventing destruction and facilitating recovery of pancreatic beta-cells under diabetic conditions.

FWF

THE ROLE OF APMAP IN ADIPOGENESIS AND ENERGY METABOLISM (STAND ALONE PROJECT: 2012-2015)

Juliane G. Bogner-Strauss

Obesity and type 2 diabetes (T2D) are strongly connected diseases and constitute an increasingly prevalent health (and economic) problem. To date, worldwide 1 billion people are affected by overweight and 250 million people by T2D. It is widely understood that obesity can lead to insulin resistance on the way to T2D. Excess food intake, a sedentary life style, and genetic factors are responsible for this development. Thus, the identification of genes that predispose individuals to obesity, insulin resistance and T2D could provide tools for developing strategies and/or therapeutics to combat obesity and its consequences. Recently, we identified APMAP (adipocyte plasma membrane-associated protein) as an important player in adipogenesis (Bogner-Strauss JG et al. Cell Mol Life Sci. 2010. 67(23):4049-4064). | Within this project, we aim to unravel the physiological function of APMAP in adipogenesis as well as lipid and glucose by generating whole body and tissue-specific APMAP-knock-out (ko) mice. We will also investigate whether APMAP-ko mice are resistant to diet-induced obesity and associated metabolic disorders. We anticipate that the characterization of our mouse models will provide new insights into the process of adipogenesis and the development of metabolic disorders which are linked to an imbalance of the amount of adipose tissue and/or to disturbed glucose metabolism. We expect that the results of our studies will provide clues for developing novel tools to fight the increasing health and economic burden of metabolic disorders.

DOCTORAL PROGRAM: METABOLIC AND CARDIOVASCULAR DISEASE (MCD) (2011-2014) LIPASES AND ADIPOGENESIS

Juliane G. Bogner-Strauss

Research: The master regulators of adipogenesis are peroxisome proliferatoractivated receptor (PPAR)-? and CCAAT/enhancer binding proteins (C/EBPs). During the last decade, several other genes which also play important roles in adipogenesis have been identified. Using transcriptome analysis of differentiating 3T3-L1 cells, we identified a couple of new genes that might play an important role in fat cell development and lipid droplet formation. The two PhD students will investigate the function of at least two yet uncharacterized candidate genes that, as we learned from preliminary data, seem to play an important role in adipogenesis. Education: The DK-MCD provides a challenging PhD education program which is unique because it (i) comprises a multidisciplinary faculty from three local universities, (ii) requires (inter)national student exchange and (iii) covers major topics in metabolic and cardiovascular disease from basic research to clinical aspects in a translational approach. We are confident that the DK-MCD will enable the PHD students to pursue careers in areas of growing importance for health and society.

GEN-AU

BIOINFORMATICS INTEGRATION NETWORK (BIN III)

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.

GENOMICS OF LIPID ASSOCIATED DISORDERS (GOLD III)

Comparative transcriptomics of models of lipid-associated disorders

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.

ncRNA: NON-PROTEIN CODING RNAS: FROM IDENTIFICATION TO FUNCTIONAL CHARACTERIZATION

Functional characterization of microRNA-mRNA pairs targeting adipogenesis and obesity Marcel Scheideler, RNA Biology Group

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 1.5 billion adults overweight and 500 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.

GOVERNMENT OF STYRIA

NANOFAT: MICRORNA DRUG DELIVERY FOR INCREASED ENERGY EXPENDITURE IN ADIPOSE TISSUE Marcel Scheideler, RNA Biology Group

The dysbalance of excessive energy intake over energy expenditure leads to overweight and obesity. Both conditions have reached epidemic proportions globally with more than one billion adults overweight (BMI > 25 kg/m2) and at least 400 million of them clinically obese (BMI > 30 kg/m2). While energy is stored in white adipose tissue (WAT), brown adipose tissue (BAT) combusts fat thus dissipating energy via non-shivering thermogenesis. Owing to new data obtained in the last couple of years, increasing energy expenditure via non-shivering thermogenesis in adipose tissue is now reconsidered as anti-obesity strategy for two reasons: (i) brown adipose tissue (BAT) has been known in rodents to dissipate caloric excess through diet-induced thermogenesis, and (ii) in contrast to early contention, healthy adult individuals possess active BAT at various sites with a potential of metabolic significance. MicroRNAs, a novel class of regulators, play a central role in the gene regulatory network. Furthermore, due to their small size and fast synthesis opportunities, it is tantalizing to use microRNAs as pharmacological reagent or target. Therefore, the overall objective of this project is the efficient nanoparticle-mediated microRNA delivery into human adipocytes.