Research

Research Laboratories

Steffen Lab

web site: http://steffen.bu.edu
principal investigator: Dr. Martin Steffen

The Immune System in COPD
COPD is the fourth leading cause of death in the U.S. It is a complex respiratory disease with a progressive airflow limitation that is associated with an abnormal inflammatory response. Disease progression is understood in broad terms: airborne respiratory irritants enter the lung and initiate tissue damage. Tissue damage results from a combination of inflammation, oxidative stress, and protease activity. However, for reasons that are unknown, only ~20% of smokers develop significant disease. What are the differences in the inflammatory responses of those that do and do not develop COPD?

Most prior studies of molecular mechanisms in COPD can be classified into two groups: those that study one cell type in great detail (e.g. macrophages) but do not provide information on other cell types, or those that explore immune response in multiple cell types simultaneously but focus on a limited number of proteins, typically a few surface markers. The very term \"immune system\" suggests that, ideally, one should study multiple immune cell types, with particular attention to the signaling mechanisms used to coordinate their activity. Current mass spectrometry technology allows the identification of hundreds of proteins from a single sample, producing a proteomic profile of the cell. We are investigating proteomic profiles from multiple immune cell types - neutrophils, B-lymphocytes, monocytes, CD4+ and CD8+ T-lymphocytes - from single individuals. The data are both comprehensive across the immune system and rich in molecular detail, and together, provides new insight into inflammation in COPD.

Serum Proteomics in Lung Cancer
Lung cancer is the leading cause of death from cancer, killing more than breast, prostate and colon cancers combined. No reliable method of early detection exists, such a test would have the potential to benefit many thousands of patients each year. Recent data suggests a multistep model for the progression of lung cancer. In this model, a rare genetic mutation eventually gives rise to a large population of cells with a proliferative advantage, followed by additional series of rare mutations and waves of clonal expansion.

This observation presents an intriguing possibility for the development of a minimally-invasive, plasma-based protein test for the early detection of lung cancer. Our search is guided by the hypothesis that the amount of a protein marker circulating in plasma is proportional to the amount of affected tissue and that based on the multistep model, large amounts of nearly-cancerous tissue will be present when the initial cancerous foci is still microscopic.

Computational Approaches to Signal Transduction
Intracellular signal transduction is achieved by networks of proteins and small molecules that transmit information from the cell surface to the nucleus, where they ultimately effect transcriptional changes. Understanding the mechanisms cells use to accomplish this important process requires a detailed molecular description of the networks involved.

We have developed a computational approach for generating models of signal transduction networks which utilizes protein-interaction maps generated from large-scale twohybrid screens and expression profiles from DNA microarrays. Networks are determined entirely by integrating protein-protein interaction data with microarray expression data, without prior knowledge of any pathway intermediates. In effect, this is equivalent to extracting subnetworks of the protein interaction dataset whose members have the most correlated expression profiles.

This technique accurately reconstructs MAP Kinase signaling networks in Saccharomyces cerevisiae. More generally, it provides a method for synthesizing molecular data, either individual transcript abundance measurements measurements or pairwise protein interactions, into higher level structures, such as pathways and networks.

We are now using this method to investigate signal transduction networks in C. elegans and the human immune system.