| |
 Mission Statement:
Directed by Dr. Avrum Spira, the Bioinformatics and Systems Biology program at the Boston University Pulmonary Center consists of group of Pulmonologists and Bioinformaticians involved in translational research into lung biology and disease. The long terms goals of this program are to apply and stimulate the development of post-genomic technologies and computational tools for translational research into human disease and to train physician-scientists and graduate students who can apply these tools in a clinical setting.
Background:
With the complete sequence of the human and other genomes recently elucidated, we have witnessed an explosion of information and high-throughput tools that are profoundly altering biomedical research and the culture of science. The reference genomes combined with advances in the biotechnology sector have produced an exponential growth in the amount and types of data available regarding biological systems. These developments are altering the paradigm of biological research, from traditional studies of single genes or pathways to large scale studies that combine data-mining of high-throughout datasets (i.e. cDNA microarray experiments) for hypothesis generation with experimental work for validation. The reference human genome has also allowed us to rapidly characterize polymorphisms across the human population, and has also enabled molecular fingerprinting technologies that can identify the precursors and consequences of normal and pathological changes in gene and protein expression.
Driven by this large and rapidly increasing amount of data over the last several years, the discipline of Bioinformatics has emerged whose goal is to apply the techniques from computer science, such as data manipulation and pattern discovery techniques, to solve problems in molecular biology. The field of Bioinformatics has now begun to move beyond the genome-wide study of individual biological components (i.e. genes or proteins) to integration of interactions and relationships between various components of the biological system, to provide an understanding of the whole biological system (i.e.“Systems Biology”).
 |
High throughput platforms employed for Systems Biology. The three major technologies responsible for rapid analysis of biological systems include mass spectrometry, sequencing, and microarrays. Examples of each technology have been listed as applied to each broad stage of biological information – DNA, RNA, and protein. |
The Bioinformatics and Systems Biology Program strives to apply and develop computational tools that can be used to mine data from high-throughput translational research studies ongoing within the Pulmonary Center. This program combines expertise in designing and running genome-wide studies of gene and protein expression (using cDNA microarray and mass spectrometry) on clinical specimens with high-throupghput data storage and analysis capabilities (see figure below). The scientists affiliated with this Program combine talents of molecular biologists with mathematicians, statisticians, epidemiologists and computer scientists. A number of the ongoing projects within the program are described below. This program along with the SMOKING-RELATED LUNG DISEASES program directed by Dr. Jerome Brody together form the Pulmonomics Lab at Boston University Medical Center.
Our program also serves to train Bioinformatics and Pathology graduate students and clinician- scientists in the application of these tools to clinical studies. In conjunction with the Dr. Charles DeLisi at the College of Engineering at BU, we have developed a Masters Program in Clinical Bioinformatics (MD track) whose goal is to train physicians who will be leaders in applying and stimulating the development of post-genomic technologies to clinical research and the practice of medicine.
Selected Ongoing Research Projects:
- The Airway Transcriptome: Developing Biomarkers for Lung Cancer and COPD: As one of the central projects within our program, the goal of this study is to profile gene expression changes occurring in intrathoracic (bronchial) and extrathoracic (buccal mucosa and nasal epithelium) airway epithelial cells in the setting of tobacco exposure and develop molecular biomarkers that can predict those smokers at risk for having or developing lung cancer and COPD. This study, performed as part of collaboration with Affymetrix (www. affymetrix.com), has defined the genome-wide impact of smoking and smoking cessation on bronchial airway epithelium (see PNAS manuscript) and has recently identified an airway signature that can serve as a highly sensitive and specific diagnostic in smokers with clinical suspicion of lung cancer.
- Mechanisms of regulation of airway epithelial gene expression: Our program has begun to explore genetic, epigenetic and post-transcriptional regulators of gene expression changes within airway epithelial cells. In collaboration with Dr. Douglas Bell at the NIEHS, we are linking gene expression profiles to SNPs in promoter regions of these genes via computational modeling and a novel high-throughput SNP platform. We are also exploring promoter methylation in these cells using a MALDI-TOF Mass Spectometry platform. Finally, we are planning to explore the role of microRNAs in post-transcriptionaly regulating gene expression in these cells using microRNA and whole genome tiling arrays.
- Constructing Biological Networks: In collaboration with Dr. James Collins, we are developing novel reverse engineering algorithms to reconstruct gene regulatory networks from airway microarray data in order to define molecular pathways that characterize smokers with lung cancer and COPD.
- Airway Proteomics: Using tandem Mass Spectometry in the Proteomics Core Facility (under the direction of Dr. Martin Steffen), we are profiling protein expression changes in airway epithelium and correlating these results to gene expression measurements produced by the experiments described above.
- Genomics and Lung Development: In collaboration with Drs. Marty Joyce Brady and Marisa Ramirez, we are profiling gene expression changes that occur in the murine lung in the perinatal period.
- Immunopathology of the Nasal Mucosa in Sarcoidosis: Together with Drs. David Serlin and Dr. Jeffrey Berman, we are studying gene expression profiles of nasal epithelium in the setting of sarcoidosis and their relationship to clinical outcome.
Expertise:
DNA microarrays
MALDI-TOF MS for high-throughput gene expression and methylation
Tandem Mass Spectometry for proteomic profiling
SNP arrays
Construction of relational databases
Reverse Engineering of Biological Networks
Principal Investigators:
Avrum Spira, MD ; The Pulmonary Center
Jerome Brody, MD; The Pulmonary Center
Gang Liu, PhD; The Pulmonary Center
Paola Sebastiani, PhD; School of Public Health, Boston University
Marc Lenburg, PhD; Department of Genetics and Genomics
Martin Steffen, MD, PhD; Department of Genetics and Genomics
Agnes Bergerat, PhD; Department of Genetics and Genomics
Marisa Ramirez, PhD; The Pulmonary Center
Marty Joyce Brady, MD; The Pulmonary Center
George O’Connor, MD; The Pulmonary Center
Karen Schlauch, PhD; Department of Genetics and Genomics
Post-Doctoral Fellows:
Frank Schembri, MD; Pulmonary Fellow
Katrina Steiling, MD; Pulmonary Fellow
Students:
Jennifer Beane (PhD candidate, Bioinformatics)
Vishal Shah (PhD candidate, Bioinformatics)
Amy Adams (PhD candidate, Bioinformatics)
Elizabeth George (PhD candidate, Bioinformatics)
Sriram Sridhar (PhD candidate, Pathology and Laboratory Medicine)
Study Cooordinator:
Martine Dumas, MPH
Collaborators (outside of BU medical center):
James Collins, PhD; College of Engineering, BU
Chunming Ding, PhD; Chinese University of Hong Kong
Douglas Bell, PhD; National Institute of Environmental Health Sciences, NC 9
Joseph Keane, MD; Trinity College, Ireland
John Beamis, MD; Lahey Clinic, Burlington, MA
Bartolome Celli and Victor Pinto-Plata; St. Elizabeth’s Hospital, Boston
Scott Tenenbaum, PhD; University at Albany-SUNY, NY
Links:
Pulmonomics lab
Selected Publications:
Brody JS, Spira A. Inflammation, Lung Cancer and COPD. Chest. 2005. In Press.
Beane J, Kadar A, DeLisi C, Spira A. Diagnostic and Prognostic Impact of high-throughput genomic and proteomic technologies in the post-genomic era. In Pincus M (ed): Henry’s Clinical Diagnosis and Management by Laboratory Methods, 21st Edition. Saunders/Elsevier, Philadelphia. 2005. In press.
Demeo D, Mariani T, Lange C, Srisuma S, Litonjua A, Celedón C, Lake S, Reilly J, Chapman H, Mecham B, Haley K, Sylvia J, Sparrow D, Spira A, Beane J, Pinto-Plata V, Speizer F, Shapiro S, Weiss S, Silverman E. The SERPINE2 gene is associated with Chronic Obstructive Pulmonary Disease. Am J Human Genetics. In press. 2005.
G Millien, A Spira, A Hinds, J Wang, MC Williams, and MI Ramirez. Alterations in gene expression in T1? knock-out? lung: a model of deficient alveolar sac formation. Submitted. 2005
Shah V., Sridhar S., Beane J., Brody J., Spira A. SIEGE: Smoking Induced Epithelial Gene Expression Database. Nucleic Acids Res. 33: D573-9. 2005
George E, Spira A, Liu G, Liu Y, Brody JS, Jean JC, and Joyce-Brady M.
KLF4, transiently activated by oxidant stress, may regulate genes required for postnatal lung development. In preparation.
Kadar A, Spira A. Smoking and the Molecular Mechanisms of Atherogenesis. In Loscalzo J (ed): Molecular Mechanisms in Atherosclerosis, The Partheon Publishing Group, Lancaster, UK. 2005. 209-220
Spira A*, Beane J*, Pinto-Plata V*, Kadar A, Liu G, Shah V, Celli B, Brody, J.S. Gene Expression Profiling of Human Lung Tissue from Smokers with Severe Emphysema. Am J Respir Cell Mol Biol. 31: 601-610. 2004. *contributed equally and should be considered co-first authors
Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, Palma J, Brody J. Effects of Cigarette Smoke on the Human Airway Epithelial Cell Transcriptome. Proc Natl Acad Sci USA. 101:10143-8, 2004
Spira, A, Beane J, Schembri F, Liu G, Yang X, Ding C, Gilman S, Cantor C, and Brody J. Noninvasive method for obtaining RNA from buccal mucosa epithelial cells for gene expression profiling. Biotechniques. 36:484-87, 2004
Hoffman A, Awad T, Spira A, Palma J, Webster T, Wright G, Buckley J, Davis R, Hubbell E, Jones W, Tibshirani R, Tompkins R, Triche T, Xiao W ,West M, Warrington J. Expression profiling — best practices for data generation and interpretation in clinical trials. Nature Reviews Genetics. 5: 229-38, 2004.
Spira A, Carroll D, Aziz Z, Liu G, Shah V, Kornfeld H, Keane J. Apoptosis Genes in Human Alveolar Macrophages Infected with Virulent or Attenuated M. tuberculosis. Am J Respir Cell Mol Biol. 29(5):545-51, 2003
Spira A*, Powell C*, Derti A, DeLisi C, Liu G, Borczuk A, Busche S, Sugarbaker D, Bueno R, Brody J. Gene Expression in lung adenocarcinomas of smokers and nonsmokers. Am J Respir Cell Mol Biol. 29:157-162, 2003 *contributed equally and should be considered co-first authors
Spira A, Yanai I, Chettier R, Wu J and DeLisi C. High-Throughput Functional Inference in the Post-Genomic Era. In Appasani K (ed): Perspectives in Gene Expression, Eaton Publishing, Westboro, MA. 2003: 345-357.
|
|
