Speaker Proposals
being Accepted!

The regulation of genes and the proteins they encode is at the core of systems biology. An understanding of the role of gene regulation in the context of the whole system as applied to disease processes will help drive therapeutic development. Integrating our knowledge of gene expression and promoter control, improving gene and protein networks, and defining the role of signal transduction will advance our ability to remedy complex diseases.

7:30  Registration & Morning Coffee

FROM GENE REGULATION TO SYSTEMS BIOLOGY

8:30 Networks at Work in Drug Discovery and Biomedicine
Chairperson: Gustavo Stolovitzky, Ph.D., Manager, IBM Functional Genomics and Systems Biology Group, IBM Research

9:20 Deciphering the Complex Roles of Transcriptional Networks in In Vivo Cardiovascular Disease Models 
Keith Jones, Ph.D., Associate Professor, Pharmacology and Cell Biophysics, University of Cincinnati
Recent progress in elucidating how specific sets of genes are co-regulated have revealed that the complex output of multiple signaling pathways mediates activation of sets of factors that activate specific genes comprising transcriptional networks. However, results from experiments using in vitro cell culture approaches do not predict the in vivo results. Presumably, this reflects the nature of signals during disease in vivo and the complex interaction of transcription factors and co-factors in multiple cell types. To dissect the mechanisms that underlie transcriptional networks in vivo, we developed a novel non-viral DNA delivery technology based upon polyglycoamidoamine (PGAA) polymers. This technology is capable of delivering DNA decoys, transgenes and siRNA, has no detectable effects upon cell viability and is efficient both in vitro and in vivo. We employ this technology, traditional transgenesis, gene array analyses and ChIP-chip approaches to delineate functional transcriptional networks in vivo. We are using this approach to address the hypothesis that different NF-B-dependent gene sets constitute stimulus-specific gene networks that underlie aspects of paradoxical pathophysiological outcomes. This in vivo strategy is generally applicable to the study of regulomics and has the potential to elucidate the specific regulatory networks that underlie disease processes in vivo and to delineate new therapeutic targets.

9:50 Validation of Gene Networks and Their Use in Drug Development.
D. Stephen Charnock-Jones, Ph.D., Co-Founder, GNI Ltd; University Reader, Department of Pathology, University of Cambridge
Endothelial cells play a key role in the regulation of physiological processes that are implicated in significant pathologies including cardiovascular disease, cancer and numerous conditions where inflammation occurs. To understand the regulatory mechanisms operating in these cells we have generated regulatory gene networks that are built from the bottom up by inferring gene-to-gene regulatory relationships from 100s of new expression array experiments. These networks reveal known and novel regulatory relationships. 

10:20 Coffee Break

10:50 Matching Ion Transport to Cell Phenotype with REST and Other Transcription Factors
David J Beech, Ph.D., Professor, Institute of Membrane & Systems Biology, University of Leeds
The vascular smooth muscle cell is an example of a cell that retains its capability to switch phenotype through adult life – from a contractile cell to a non-contractile, proliferating and migratory cell. This capability is important in physiology but also contributes substantially to vascular diseases including neointimal hyperplasia. An emerging feature of the phenotypic switch is that it is accompanied by change in the selection of ion channels made by the cell. Some of the change is known to be functionally important because blocking key ion channels suppresses proliferation, migration and neointimal hyperplasia. Other cell types undergo similar changes and so there may be common underlying mechanisms. Regulatory networks at the transcriptional level are clearly implicated and emerging features will be reviewed. The lecture will focus on REST (repressor element-1 transcription factor), recently shown to be a repressor of the KCNN4 gene, which encodes a critical potassium channel (KCa3.1) in cell proliferation. REST is down-regulated in cell proliferation and regulates expression of  ion transport associated with cell phenotype switching.

11:20 Examination Of Structure Function Relationships Of Medicines By Comparing Drug-Induced Protein-Network Topologies
Anton J. Fliri, Ph.D., Research Fellow, Neuroscience, Pfizer Inc.
Discovery of medicines requires a deep understanding of the information exchange between protein and organ systems networks. Moreover, medicinal chemists trying to integrate this knowledge need tools for assessing effects of medicines on network systems and for translating system knowledge into new drug designs. Herein we present a strategy for comparing protein-network topology information for pharmacologically related medicines. This comparison provides information on likely functions associated with certain signal transduction-network topologies and presents a new perspective on the relationship between intended and unintended drug effects.

11:50 – 12:05 Technology Workshop

12:05 – 1:35 Lunch on Your Own or Technology Workshop 
(Sponsorship Available) 

GENOMIC PROFILING

1:30 Chairperson: D. Stephen Charnock-Jones, Ph.D., Co-Founder, GNI Ltd; University Reader, Department of Pathology, University of Cambridge

1:40 Genomic Profiling of Somatic Changes in Human Tumors
John Chant, Ph.D., Associate Director, Molecular Biology, Genentech, Inc.

2:10 Identification of Overexpression of Orphan G Protein-Coupled Receptor GPR49 in Human Colon and Ovarian Primary Tumors
Ahmed A. Samatar, Ph.D., Associate Principal Scientist, Oncology Department, Schering-Plough Research Institute
Gene expression profiling technique was used to probe differences in transcriptional output between 15 panels of colon tumor and matched normal colon tissues. GPR49, an orphan G Protein-Coupled Receptor (GPCR) was identified as over-expressed in 66% colon tumors compared with normal colon tissues. The selective over-expression of GPR49 in tumor tissues was further revealed by specific immunohistochemical staining of colon and ovarian tumor tissues. Down regulation of GPR49 mRNA by RNAi technology induced cell death in the tumor cells overexpressing the receptor. These novel findings provide a foundation for further studies and suggest a potential role for GPR49 in tumorigenesis.

DATABASE AND TECHNOLOGICAL APPROACHES

2:40 Chairperson: John F. Russell, Executive Editor, Bio IT World

2:45 Microarray Analysis Revealing Molecular Mechanisms Underlying Diseases Processes
Klaus J. W. May, Ph.D., Chief Business Officer, Genomatix Software GmbH
Micro array-based analyses are a standard approach in modern molecular biology. However, so far results are still short of fulfilling the expectations. Microarray mining is a challenging task because of the intrinsic superposition of several biological processes mirrored in the data. General aims of microarray analysis always comprise classification and diagnostics of samples, gaining insight into regulatory networks and finally learning more about disease mechanisms. Pathway-oriented analysis is currently one of the most promising approaches. Based on an example, the analysis of colon cancer versus normal tissue using new exon arrays, we present a combinatorial strategy which applies complete up-to-date single probe annotation as a first step, followed by data driven pathway and network mining in combination with genomic regulatory sequence analysis. The results show a promising way of digging deep into disease mechanisms by unveiling relevant pathways and making use of advanced chip analysis, genome annotation and promoter analysis in an itegrative way.

3:10 Refreshment Break

3:40 Identification of Defective Signaling Pathways in the Aggressive Uveal Melanoma
Anton Yuryev, Ph.D., Director of Application Science Department, Application Science, Ariadne Genomics
Uveal melanoma is the most common intraocular cancer among adults and results in a death rate of 50%. The molecular basis of the tumor aggressiveness was studied using expression data obtained from two aggressive uveal melanoma cell lines and one non-aggressive tumor to identify the mechanisms underlying its metastasis. Using the ResNet 4.0 molecular interaction network database we have identified a network containing 53 differentially expressed proteins that function in cell-matrix and cell-cell adhesion. These proteins are downregulated in the aggressive cell lines when growing in 3D culture in contrast to the non-aggressive tumors. This suggests that the downregulation of these proteins is responsible for the loss of substrate attachment and therefore increases the tumor invasiveness. Moreover, we find that that SP1 transcription factor is known to regulate transcription of 24 out of 53 genes in ResNet 4.0 indicating that the defects in SP1 signaling pathways may contribute to the aggressiveness of the uveal melanoma. We confirm that SP1 is a major transcriptional regulator in aggressive uveal melanoma tumors using a novel statistical algorithm to identify major regulators for the differentially expressed genes in the transcriptional network.

4:05 Characterization of Genome-Wide Promoter Occupancy: Implications for Gene Transcription Control and Disease Pathways
Lingxun Duan, M.D., Executive Vice President, Aviva Systems Biology
A novel full-genome human promoter array technology termed ChIP-GLAS (ChIP-DSL) permits detection of DNA-protein interactions in vivo using two-orders of magnitude less material than that required by the standard ChIP-on-chip procedure. Applying this technology to profile both general and sequence-specific transcription factors reveals a hidden world of DNA-protein interactions. The data presented will give new insight into transcriptional and epigenetic mechanisms providing a powerful tool with which to decode the molecular underpinnings of disease, including cancer.

CHARTING A FUTURE COURSE

4:30 Stochasticity in Signaling Pathways and Gene Regulation: The NFêB Example and the Principle of Stochastic Robustness 
Marek Kimmel, Ph.D., FASA, Professor, Department of Statistics, Rice University
This talk summarizes modeling studies carried out in my group, which elucidate the role of stochastic dynamics in transcription regulation and signal transduction. In particular, we argue that stochasticity plays a major role in making signaling pathways robust to fluctuations in signal level. The main biological object we studied is the NFêB regulatory module. NFêB is a transcription factor controlling a range of immune responses including inflammation and apoptosis. It is regulated by at least two negative feedback loops involving IêBá and A20. This mode of regulation results in serial waves of expression of NFêB responsive genes. Single-cells experiments carried out by several groups prove that stochastic effects play important role in NFêB regulation. The stochastic event of gene activation results in a burst of mRNA molecules, each serving as a template for numerous protein molecules. Another potential source of variability is receptors activation. At low dose stimulation, important in cell to cell signaling, the number of active receptors can be low enough to introduce substantial noise to downstream signaling. Modeling confirms the large variability in cell responses and shows that no cell behaves like an “average” cell. Stochastic robustness is a resulting mechanism that assures the minimal response to the signal. Decreasing magnitude of the signal below certain threshold only causes lowering of the probability but not of the level of single-cell response. Stochastic robustness allows individual cells to respond differently to the same stimulus, but makes their individual responses well-defined. Both effects can be important: Diversity in cell responses causes the tissue defense to be harder to overcome by simple programs of viruses and other pathogens. Focused single-cell responses make cells decide their individual fates such as apoptosis or proliferation.4:30 To Be Announced

 

Featured Presentation

5:00 The DREAM Project: Assessing the Accuracy of Reverse Engineering Methods Gustavo Stolovitzky, Ph.D., Manager, IBM Functional Genomics and Systems Biology Group, IBM Research Many of the efforts in the field of systems biology focus on the inference of networks of interactions of molecular species from biological data. A logical place to start is to produce a coarse diagram or map of the connections (physical, chemical or statistical) between molecular species of the network, without worrying, initially, about the detailed kinetics. A number of methods have been developed, and continue to be developed to disentangle the connectivity maps within the cell. To organize the sea of methods and help the community understand the merits and pitfalls of one method versus the other, a group of systems biologists have started what we call the DREAM (Dialogue on Reverse Engineering Assessment Methods) project. In this presentation we will discuss the different thrusts of this project and the results of the first DREAM conference, held on September 7 and 8.

5:30 Close of Symposium