The highly complementary investigators' expertise, the large variety of methodologies and tools developed by the Center to dissect and map cellular pathways, and their integration into a modular and interoperable software platform will provide a powerful framework to tackle a variety of relevant biomedical problems. We have identified three Driving Biological Projects (DBPs) that provide an archetype of the range of biomedical problems that would benefit from the MAGNet activities at different levels of granularity. We summarize the core criteria that we have adopted in selecting this first set of projects. With some refinement, resulting from these first three engagements, we expect that these criteria can be effective in guiding the selection of future Center related projects.
Biomedical relevance and scientific merit
: DBPs should address biomedically relevant problems that will uniquely benefit from the ability to dissect specific intra- or inter-cellular interactions.Ability to drive computational biology and bioinformatics innovation
: DBPs should drive the creation of new computational algorithms and data analysis methodologies, with specific emphasis on the integration of distinct data modalities.Addressing all levels of granularity of the Center's Network Centric vision
: different DBPs should address distinct ranges of granularity of the underlying biological processes, from the study of specific structure based interactions, to the elucidation of cellular pathways on model organisms, to the identification of modular control of cellular functions and processes, all the way to the dissection of complex disease based on genomic pathway information.Feasibility and pertinence to the MAGNet Center scientific mission
: DBPs should uniquely benefit from the MAGNet tools and investigator expertise.
Based on these criteria, the Center has selected three DBPs (briefly discussed below) to be the focus of the initial research activity.
STURCTURAL AND ENERGETIC BASIS OF CADHERIN BINDING SPECIFICITY
The goal of this project is to understand the structural and energetic basis of cell-cell adhesion mediated by the cadherin family of cell adhesion proteins. Adhesion between cadherin family members, primarily through selective homophilic interaction, provides a key driving force in the development of tissue architecture. It is the subtle differences among family members that are responsible for this crucial selectivity, which guides tissue development. Neither sequence analysis nor observations on known crystal structures have been able to reveal the structural and energetic origins of cadherin specificity. It has become clear that computational studies are required both to generate testable hypotheses and to interpret experimental results once they are obtained. We propose a joint program involving the energetic analysis of protein-protein interfaces, structure prediction, x-ray crystallography, biophysical measurements of binding and cell-sorting experiments. Possible specificity determinants will be identified, mutant proteins will be designed and evaluated for their binding propensities, and new crystal structures will be determined. The experiments will provide data to test quantitative theoretical predictions as well as qualitative concepts. In parallel, the theory will play a crucial role in driving and interpreting experiments. These questions and the nature of the experimental and theoretical challenges are quite general in nature. Indeed understanding how specificity is coded within protein families is a central molecular question that relates to the understanding of biological networks, the common theme of the MAGNet Center we propose to establish.
REGULATORY MODULES IN NORMAL AND TRANSFORMED B-CELLS
This project addresses a broad biological systems problem by attempting to identify conserved functional modules within Human B-Cell gene regulatory networks especially in relation to the Germinal Centers, a key structure for antibody mediated immune response and a target of transformation in B-Cell lymphomas. This will be accomplished by integrating several MAGNet developed bioinformatics methodologies. We plan to integrate (a) clues from information theoretic reverse-engineering methods applied to large microarray expression profile set (~400 microarrays) of normal, tumor-related, and experimentally manipulated B cells, (b) clues from advanced natural language-based data-mining algorithms applied to a large literature collection, and (c) clues from protein-protein and protein-DNA interaction databases. Modules that are disregulated in a variety of Germinal Center-related tumors will then be identified using expression analysis algorithms supported in geWorkbench. Finally, candidate module control genes will be identified using a combination of in-silico and invitro techniques.
GENOMIC AND BIOINFORMATICS SOLUTIONS TO THE SEARCH FOR GENETIC DETERMINANTS OF COMMON, HERITABLE DISORDERS
We will develop new disease gene pathway based bioinformatics approaches developed in the Center. The specific goal will be the identification of genes, and gene pathways, that harbor heritable determinants of two common, debilitating disorders of the nervous system, Alzheimer's disease (AD) and Autism plus related spectrum disorders (ASD). The approach will include the use of convergent bioinformatics, computational, genetic and genomic data to predict genes and gene combinations likely to harbor disease-related genetic variation, together with statistical and computational methods to detect and evaluate such datasets. For both studies, we will deploy a battery of bioinformatics and computational approaches that will be incorporated into the geWorkbench platform, to detect and evaluate disease-related genetic variation.
