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Proposal

 

Advance notice: Computational Biology in Regenerative Medicine

The International Graduate College Rostock-Shanghai entitled "Computational biology in regenerative medicine" brings clinical and basic research expertise on human adult stem cell functions in cardiology, haematology and oncology together with established research projects in tumour biology and in comparative genome analysis of autoimmune diseases. This experimental expertise will be combined with expert knowledge on bioinformatics and computational biology at the renowned Bioinformation Center of Shanghai Institutes for Biological Sciences.

Within several years the Medical Faculty of Rostock has established an internationally recognizable expertise in regenerative medicine i. clinically in stem cell therapy of myocardial infarctions (Freund, Nienaber, Stamm, Steinhoff) and ii. experimentally in functional genome analysis of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and diabetes (Glocker, Ibrahim, Tiedge, Zettl) as well as degenerative diseases (Müller-Hilke, Pützer). Both areas are supported by a strong integrative technology platform initially established at the Proteome Center Rostock (www.pzr.uni-rostock.de). Established expertise on transcriptome and proteome analysis has recently been complemented and extended by core facilities i.e. animal facility (Vollmar) and expert knowledge in electron microscopy (Jonas), cell biology (Lorenz, Rychly), vectorology and gene therapy (Pützer). In addition, knowledge and studies of principle mechanisms in gene regulation (Thiesen) and signal transduction (Pützer, Jaster, Bittorf/Tiedge) are brought together with clinically relevant disease mechanisms upon specific tumour systems (Boltze, Emmrich, Junghanß) and comparative genomic approaches (Ibrahim). Ongoing in-depth analysis of transcriptional networks and gene functions in human stem cell and tissue development in combination with siRNA knockdown experiments will be key technologies for a comparative understanding of molecular processes and regenerative mechanisms in tumour therapy and autoimmune diseases opening perspectives for novel sophisticated therapeutic strategies. Wet lab expertise mainly employed by projects conducted in Rostock will be combined with dry lab expertise established over the last years at the Bioinformation Center of Shanghai Institutes for Biological Sciences.

Ten interdisciplinary work packages (W1-10) have been condensed governing data acquisition and validation processes of numerous wet and dry lab research and Ph.D. projects. In addition, these work packages are considered to serve as frame structures for the integrative research projects as well, and are used to assign credit points to lectures, seminars and practical workshops for Ph.D. students joining the international graduate college in Shanghai and Rostock. The Bioinformation Center in Shanghai has developed structured concepts of a web-based information platform which will be used for a continuous exchange of data and for teaching in combination with focussed workshops. Since the interdisciplinary Ph.D. projects include wet and dry lab components, the research projects themselves will encourage the Ph.D. students in Rostock and Shanghai to collaborate closely with each other. Graduate students in Rostock should gain an intensive education and training in computational biology by acquiring an in-depth knowledge in terminologies, techniques, tools and data bases to be commonly used in computational sciences whereas students in China should become familiar with research strategies commonly employed in functional and comparative genome analysis of multifactorial polygenic diseases. Thus, the Bioinformation Center in Shanghai has an integrative function for the research projects which will be assigned to particular topics of the 10 work packages outlined below. These work packages have been approved by our colleagues in Shanghai in response to expertise presented by us and currently being gathered at the University of Rostock.

As notable in the subtitle "From functional and comparative genome analysis to a holistic understanding of human differentiation and disease processes", one of the main objectives of this International Graduate College Rostock - Shanghai is focussed on elucidating human differentiation and disease processes in multilevel interdisciplinary approaches by studying stem cell differentiation processes and comparing related dysregulated mechanisms and pathways in tumour systems as well as in autoimmune diseases under study. Hereto, a common platform in computational biology will be made available in this research and teaching network supported by the dedication and commitment of our colleagues in Shanghai. The nature of this network is supported as well by the interconnectivity of the work packages utilized. Since the principle investigators will assign their Ph.D. projects (R1-R16) to at least two and more work packages, a high degree of innovative power will be reinforced within this international graduate college. Finally, experimental data in conjunction with innovative ideas created within these Ph.D. programs will direct the improvement of computational biology tools. A sophisticated laboratory information management system (LIMS) has been established at the Proteome Center Rostock enabling both sides in Rostock and Shanghai to share experimentally and computationally derived data sets at the same time. Ph.D. projects of our colleagues in Shanghai will be instrumental in determining highly focussed projects assigned to the work packages (W1-10) described below, including assignments of Chinese expert knowledge.

Work package 1: "Biological data integration and visualization" (Yixue Li, Weizhong He) Establishment of an integrative data source of world knowledge on human differentiation processes and programs from the embryonic stem cell to differentiated tissues; high-performance biological data search engine and visualization system as an interface to public databases (e.g. cDNA, protein, 3D structure, gene expression, post-translational modifications databases) with integration of bioinformatic tools (open-source and commercial software) (Ph.D. projects: R4, R6, R9, R12, R14, R16)

Work package 2: "Workflow technology for flexible biological data analyzing processes"
(Yixue Li, Weizhong He). Establishing grid based computational infrastructures for the construction of distributive and flexible biological workflows integrated commercial or open-source biological software and databases, which can be used for handling laboratory information processes, and building data analysis platform (Ph.D. projects: R4, R7, R12, R10)

Work package 3: "Modelling of disease related gene regulation networks" (Yixue Li, Zhiwei Cao). Construction of dynamic network models based on data mining from laboratory experiments , databases and the scientific literature. Development of novel methods, algorithms to extract the relationship and association among all data sets. The focus will be to understand the dysregulation of regulatory processes and its adaptive evolution that is at the heart of disease etiology (Ph.D. projects: R5-R10, R12, R13, R15)

Workpackage 4: "Biological pathway mapping and mechanisms simulation" (Ying Jiang, Zhiwei Cao and Weizhong He). Mapping laboratory data onto biological pathways (e.g. signal transduction, tissue-specific and transcriptional/regulatory pathways). Construction of suitable mathematical models to simulate their dynamic properties. Subclassification of pathways based on their characteristics. Description/evaluation of crosstalk between pathways (Ph.D. projects: R1-R5, R7, R15,).

Work package 5: "Disease profiling based on genome, transcriptome and proteome data for a family of transcriptional repressors" (Yixue Li, Yang Zhong and Guoping Zhao). Analysis of the characteristic gene expression signatures on the transcriptome and proteome levels during differentiation and in dysregulated cellular phenotypes. Description of their tissue distribution on the RNA and protein levels. Evaluation of their functional relevance in stem cell differentiation (Ph.D. projects: R4, R5, R10, R11)

Work package 6: "Disease related protein-protein interaction network and posttranslational modifications" (Yixue Li, Yang Zhong). In-depth studies on protein complexes relevant in the dysregulated cellular phenotypes. Parameters include composition of complexes, posttranslational modifications of individual members and structure/function relationship, ontology of interaction (Ph.D. projects: R6-R8, R10,R11)

Work package 7: "Epigenetic properties of dysregulated cellular phenotypes" (Yixue Li, Ying Jiang, Weizhong He, Guoping Zhao). Impact of DNA methylation and histone modification on the dysregulated state of pathways in disease
(Ph.D. projects: R12, R13, R14, R16)

Work package 8: "Novel methods for disease related gene and marker identification" (Yixue Li, Guoping Zhao, Ying Jiang). Development and advancement of methods to identify susceptibility genes and to assess their biological impact. Analysis of animal models of multifactorial and polygenic human diseases (Ph.D. projects: R9, R12, R13, R15)

Work package 9: "Post-transcriptional modes of gene regulation in disease" (Ying Jiang, Weizhong He). Investigation of regulatory mechanisms acting on or through RNA (miRNA, antisense transcripts), molecular mechanisms of gene regulation, microRNA, siRNA studies, related transcriptional networks (Ph.D. projects: R6-R11, R15)

Work package 10. "Systems biology and complex biological system modeling and simulation" (Yixue Li, Yang Zhong, Guoping Zhao, Zhiwei Cao). Interrelationship of RNA world versus protein world, hypothesis/evolution of life, basic rules of life (Ph.D. projects: R4, R14, R16)


These work packages (W1-W10) will encompass Ph.D projects conducted in Shanghai as well as in Rostock. The final application will outline the objectives to be achieved. Ph.D. Projects (R1-R16) will be described in greater depth in the final application as well as the assignments and integrations of Ph.D. projects funded by other resources. Current running titles are shown below and are grouped in four categories: i. Stem cell research; ii. Oncology and iii. Autoimmune diseases with Ph.D. projects: R1-R16.

Computational and Functional Genome Analysis in Cluster I:
R00: Pathways and networks (Thiesen)
R4 : Transcriptional repressors (Lorenz)
R10: Phosphorylation states (Glocker)

Stem cell research in Cluster II:
R1 : Haematology and oncology (Junghanss, Freund, Koczan)
R2 : Cardiosurgery (Stamm, Steinhoff)
R3 : Cardiology (Koczan, Nienaber)
R5 : Neurodegenerative Disorders (Pützer)

Oncology in Cluster III:
R6 : Melanoma (Gross, Kunz, Pützer)
R7 : Pancreatic cancer (Jaster, Emmrich)
R8 : Colon cancer (Linnebacher, Klar)
R9 : Mammary cancer (Reimer, Fietkau, Gerber)

Autoimmune and degenerative diseases in Cluster IV:
R11: Alzheimer's disease (Pahnke) R12: Comparative genomics (Ibrahim)
R13: Osteoarthritis (Mueller-Hilke)
R14: Multiple sclerosis (Zettl)
R15: Diabetes mellitus (Tiedge)
R16: Rheumatoid arthritis (Glocker)

The Ph.D. training program of the international graduate college will be on one side tightly connected to the Graduate School currently being established at the Medical Faculty and the Natural Science Faculty of the University of Rostock in conjunction with the Universities of Lübeck and Greifswald as on the other side with the Ph.D. teaching program assigned to the Ph.D. programs in computational biology and bioinformatics at the Bioinformation Center of Shanghai Institutes for Biological Sciences. Objectives, milestones and deliverables of the Ph.D. teaching program as well as the interdisciplinary nature and putative synergisms between different wet lab clusters as well as the strong expertise of the dry lab component supplied by our colleagues in Shanghai will be presented and outlined in the final application.

Objectives of this International Graduate College Rostock - Shanghai are i. to develop a holistic understanding of human differentiation and disease processes, ii. to determine the robustness and functional relevance of transcriptional and regulatory pathways in normal and disease states, iii. to establish a teaching and research platform that explores the scientific value of functional and comparative genome projects together with expert knowledge in computational biology - Finally, Ph.D. students will learn how to cope with genome-wide data acquisitions and their relevance in the disease-management of individual patients on the way to a genome-oriented individualized medicine.



 




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