Personnel

Jennifer Kiesel

Dhrubamitra Chatterjee

Projects

Systems Biology of Macrophage Development & Inflammatory Response:

Macrophages play an important and multifunctional role in health and disease.  The best-known role is in innate immunity where they act as phagocytes and inflammatory cells.  In addition, they also act as a lynch pin between innate and adaptive immunity as antigen presenting cells (APC).  Macrophages also have a key function in the uptake and clearance of cholesterol interacting with low-density lipoproteins (LDL) as foam cells. Finally, macrophages can also be differentiated to become osteoclasts that function to absorb or degrade bone during remodeling. 
Our group is interested in using animal models to study the differentiation of monocytes into macrophages and the subsequent development of macrophages under various physiological conditions.   We will utilize genomics, gene expression profiling, proteomics and the tools of systems biology to develop quantitative mathematical and statistical models of macrophage development. 
While this process is understood in detail at the cellular or phenotypic level, only a few key molecular players have been identified to date.   Our goal is to use global measurements from microarrays and proteomics to infer the underlying molecular program that regulates homeostasis and drives the differentiation.   One of the key players in all the processes mentioned above is NFkB; it is activated early in all the development pathways.  Therefore, a central question is: how is the specificity of the outcome determined?  What set of signals and downstream events drive the macrophage towards any given differentiation program?  How robust is this program and how many subsystems are there? How are these signals integrated (spatial compartmentalization and parallel processing), and how do they determine the fate?
In order to generate quantitative models our group is also interested developing algorithms for network inference using graph theoretic approaches and Bayesian statistics. Mathematics to model complex circuits have been previously developed, however, many of these have not been applied to biological networks.  Biological systems use feedback loops and other regulatory mechanisms; we will also develop methods to deal with these mathematically.   The systems biology approach combines computational biology and bioinformatics, systems and control theory and modeling methods to develop a coherent and causal picture of this important biological phenomenon.  

The development of macrophages to osteoaclasts and inflammation response of osteoclasts is a collaboration with Yousef Abu-Amer (Washington University School of Medicine in St. Louis).

Redox Regulation in Cyanobacteria and Plants:

Redox homeostasis is central to the overall functions of all oxygenic organisms.  We plan to undertake a systems approach to analyze the impact of cellular redox status on the overall function of the oxygenic photosynthetic organisms.  Our initial focus will be on the cyanobacterium Synechocystis 6803, with subsequent applications in the understanding of the biology of Arabidopsis, a vascular plant, and Physcomitrella, a non-vascular plant.  Synechocystis 6803 has a completely sequenced genome and is amenable to high-throughput genome level manipulations.  Although the detailed inventory of the genes, transcripts and proteins are available for Synechocystis, it is inadequate to comprehend the organizational hierarchy of the complex functions of this organism.  Our approach to resolve this gap in our fundamental knowledge is multidisciplinary. We propose to infer a gene regulatory network in cyanobacteria that will include identification of the sensing and signaling pathways.  Further, a gene regulatory network will be independently generated in Arabidopsis, and the conservation of the genes and interactions will be evaluated. We propose to validate the network and the contribution of the network modules to the overall redox regulation and extend the model to Physcomitrella.  Such an iterative process is expected to generate fundamental insights into the organization and function of the redox control network (RCN) in these organisms.  Furthermore, such an approach, first to model an RCN in cyanobacteria, and then to  extend it to plants, will highlight the conserved nature, or lack thereof, of these processes during the evolution of land plants.

This project is funded by NSF Frontiers in Integrative Biological Research (FIBR) project. The principal investigator on this project is Himadri Pakrasi, and the coinvestigators are Ralph Quatrano, Bijoy Ghosh, (all at Washington University in Saint Louis), Ken Belanger (at Colgate University) and Rajeev Aurora. For more information on this project please visit the Sysbio web site at Washington University.

Coordinates

Resources and Downloads

A Light Regulated Network in Cyanobacteria (OMICS: A Journal of Integrative Biology)
The supporting information and an interactive network navigator are available

Python Documentation