GOALS OF SBCNY

From the grant application

The goals of the Systems Biology Center New York are to develop and disseminate approaches that provide a mechanistic understanding of how molecular interactions within regulatory networks in cells lead to the physiological function of tissues and organs, and how therapeutic agents affect cellular regulatory networks to alter pathophysiological states i.e. "the therapeutic implications of the design logic of scalability in mammalian systems".

The research focus of SBCNY will be on the development and analysis of scalable models to identify regulatory network motifs and how they are reconfigured by drugs. Models will originate from experimentally measured parameters, and the predictions of models will be used to develop experiments that shed light on the design logic of the system. We have chosen such an approach because it builds on previous successes by members of the SBCNY, including the identification of regulatory motifs such as gates and switches arising from positive feedback loops. In these cases, the subsequent experimental verification of the model predictions supports the general strategy that has allowed us to identify new regulatory network motifs within signaling networks such as gates, which have been verified experimentally and play a major role in physiological functions, such as long-term potentiation of synaptic transmission. We have also used this approach to identify a positive feedback loop that functions as a flexible switch in a proliferative pathway in fibroblasts. Several anticancer-drugs are targeted at components in this regulatory motif. Positive feedback loops in signaling pathways can also function as developmental switches. Such signaling networks are "tunable", with different parts of the network activated by different stimuli. Similarly, work by Kaplan and colleagues on neuronal networks in the visual cortex suggest that facilitatory, probably tunable feedback is common. Graph theory-based analysis by Alon and co-workers has shown that such regulatory network motifs are the building blocks of networks suggesting that an improved understanding of the physiological function of cells and tissue can come from considering the regulatory motifs. This approach of studying regulatory motifs complements statistical approaches that track and rank signaling pathways that control phenotypic behavior.

Aim 1

Conduct transdisciplinary research to advance our ability to represent cellular and tissue processes mathematically and explain how drugs perturb these processes. For this we will create and analyze a cluster of models across scales to study the dynamic topology of regulatory network motifs and how information processing within the network results in cellular behaviors that propagate across scales to yield tissue and organ behavior. Specifically, we will focus on the role of components that are drug targets and participants in regulatory network motifs to understand how drug interactions with these components lead to reconfiguration of network motifs and altered physiology. We will have four research projects, each of which has a training and outreach component by integration of short-term (3-6 months) researchers into these projects. This integration will allow us to train interested researchers at the participating institutions and other interested extramural scientists.

Aim 2

Continue the development of a large-scale database of direct mammalian interactions, building on our current database of 11,000 high-confidence interactions between 6,000 components. We will develop novel tools to construct, analyze and visualize networks and network motifs at various scales of organization. These tools will range from desktop applications and web-based tools, databases, and programs for massively parallel computing using clusters of 1000 nodes or more (e.g. IBM BlueGene). We will develop parallel programs for computing deterministic and hybrid models for large (>1000 components) networks.

Aim 3

Continue the development and implementation multivariable experiments at the proteomic and genomic levels, and gather kinetic parameters both in vitro and in vivo to obtain systems level experimental description of the networks being studied in the research projects in Aim 1.

Aim 4

Develop a novel curriculum that can be used for the teaching of systems biology of physiology, pathophysiology and pharmacology. The centerpiece of this program will be an integrated course that will use selected examples in a problem-based interactive learning format to cover cellular regulatory systems, physiology, pharmacology, and mathematical modeling across scales. This course will lead to customized mini-workshops for individualized training, which in turn lead to feasibility projects that will be connected to the Center and funded by it. Flexible entry at each stage will be available. The integrated training will be broad-based, with components focused on graduate students, postdoctoral fellows, and other investigators including PIs and educators who teach both undergraduate and graduate courses.

Aim 5

Develop and conduct two workshops per year geared towards the introduction of systems biology approaches into ongoing research projects in the experimental laboratories of workshop participants, or foster the training of physical and mathematical scientists in experimental techniques used in Systems Biology research. These workshops will be open to all faculty members at participating institutions, as well as extramural researchers.

Aim 6

Introduce senior undergraduate students to research in Systems Biology by funding and developing summer undergraduate internships, in conjunction with the Biomedical Engineering Program of CCNY and the colleges of the CUNY system. There will be special emphasis on attracting under-represented minority students to this program.