Daniel Baugh Institute
Contact
1020 Locust Street
Jefferson Alumni Hall, Room 381
Philadelphia, PA 19107
- 215-503-7823
- 215-503-2636 (fax)
Research at the Daniel Baugh Institute
We are interested in relating molecular events to their physiological significance. To this end, we employ current system-wide, high throughput data acquisition approaches along with computational analysis. We use genome-scale data sets to construct computational system models of regulatory networks in mammalian cells. The following is a synopsis of current projects in the institute. These projects comprise experimental, computational and informatics domains to varying extents.
We integrate system-wide information from different data sources including gene and microRNA expression, transcription factor activity, genome-wide location analysis, cytokine profiles, and single cell data sets, to develop computational models of intracellular regulatory networks, cell-cell interactions, and organ physiology. We also develop new analysis methods that provide novel insights into the underlying control principles and regulatory mechanisms of physiological behavior.
- Central autonomic regulatory networks driving the development and maintenance of hypertension
- Liver function, repair and regeneration altered by adaptation to alcohol consumption
- Genomic studies of toxicological insult and brain development
- Effects of alcohol on brain systems involved with addictive and withdrawal processes
- Intracellular processes induced by growth factor signaling
DBI Researchers
James S. Schwaber, PhD
Dr. Schwaber is a Professor of Pathology, Cell Biology and Anatomy at Thomas Jefferson University, where he is the Director of the Daniel Baugh Institute for Functional Genomics and Computational Biology. He received his BA from the University of Illinois, his PhD from the University of Miami in Neuroscience working under Dr. Neil Schneiderman, and postdoctoral training at the University of Virginia under Drs. David Cohen and John Jane. He spent 20 years in the E.I. DuPont Company where he, sequentially, (1) co-developed in the Neurobiology Group the business plan that was the platform to launch the Cephalon Pharmaceutical Company; (2) participated in the Cardiovascular Sciences group that developed the anti-hypertensive drug losartan; (3) was awarded patents for imaging methods that were licensed to form businesses that perform neuroanatomical mapping and imaging; (4) hosted a conference in 1986 at DuPont to coordinate research among investigators interested in digital brain atlas technology that has come into use in MRI; (5) led an interdisciplinary “Core Genomics” computational biology team with projects in ag-biotech and microbial metabolism, as well as pharma; and (6) hosted a ONR-NSF-DuPont sponsored funding initiative planning workshop “Gene Networks and Cellular Controls” in 1996. In 2000, Dr. Schwaber joined the faculty of TJU and (1) initiated the computational and genomics focus of the Daniel Baugh Institute; (2) participated in the DARPA Bio-COMP initiative; and (3) received NIH BISTI initiative funding to initiate and develop a cooperative research and training program with the University of Delaware to exploit their complementary strengths in medicine and engineering.
Dr. Schwaber’s main interest is in the emotional–visceral neuraxis and disorders involving this interaction, including those related to stress and autonomic imbalance in neurogenic contributions to hypertension, addiction and withdrawal from the dependent state, and neurodegenerative conditions including epilepsy. In recent years he has discovered a significant and long-lasting innate neuroimmune component with major contributions to these disturbances. As a result, he studies these processes as tissue scale network interactions of epithelial, microglia and astrocyte, as well as neuronal cells.
Over the span of time, Dr. Schwaber has gained and used neurophysiological, neuroanatomical and neural network modeling approaches, including integration of these data into physiological models of cardiorespiratory regulation and of the respiratory rhythm and pattern generator. Currently, he brings a systems biology perspective to all projects, including high-throughput data acquisition, genomics measures around transcriptional regulation including signaling protein networks, gene expression, miRNA, ChIP using next gen sequencing and other high throughput instrumentation, and computational analyses and gene regulatory network modeling/simulation. Recently he has evolved technologies to enable single cell analysis, and by taking these measures across large numbers of neurons, he has developed new perspectives on the sources and meaning of variability or heterogeneity in neuronal populations-phenotypes.
Dr. Schwaber believes the evidence supports the view that cell phenotype arises from the combinatorial input history of the cell and is present as a "state-memory" in the transcriptome defined as RNA and regulatory proteins. In the case of central neuronal populations he has interpreted the data in a way that leads to a novel view of "the neural code", replacing spike rate coding with pattern coding by the population.
Jan B. Hoek, PhD
Dr. Hoek received his early training with some of the leading investigators of the day in metabolism (HA Krebs, University of Oxford, UK), mitochondrial function (JM Tager and EC Slater, University of Amsterdam) and oxidative stress (L Ernster, University of Stockholm). Through his career, he has retained an active interest in the impact of metabolic deregulation on disease. His work emphasizes the functional interconnections between cell signaling, metabolism and mitochondrial function. Currently, the focus of his lab is the elucidation of the molecular and cellular mechanisms underlying alcohol-induced cell and tissue dysfunction leading to alcohol-related diseases, specifically in the context of the regeneration response to liver damage by partial hepatectomy. He applies a broad range of experimental and theoretical approaches to characterize changes in cell signaling, energy metabolism and stress signals associated with acute and chronic ethanol consumption in liver and other tissues and its effects on tissue repair responses to injury. Gene expression and microRNA profiling are used to characterize the transcriptional and microRNA regulatory network, and more specifically, to resolve the contributions of individual cells and cell types in the liver to the integrated proliferative response and to understand the nature of the defects in regeneration associated with chronic alcohol treatment.
At the cellular level, a computational modeling approach is being applied to identify feedback loops in cell signaling and metabolic networks that may affect the stability and response strength of cells. Dr. Hoek’s interest in cell signaling and its deregulation in liver disease was the initial stimulus for an emphasis on a computational modeling analysis of cell signaling networks. This approach relies on a close collaboration with theoretical biologists and aims at integrating experimental and computational studies of the cell signaling responses in order to arrive at a more quantitative understanding of the network features of the signaling machinery. This work resulted in one of the first publications to provide a detailed computational model of the upstream elements of the EGF receptor signaling network (Kholodenko et al, J Biol Chem 1999), at a time when the potential of that approach was barely appreciated.
The further elaboration of the analysis of the EGFR signaling network in ongoing collaborations with the computational biology group of Dr. Boris Kholodenko (now at University College Dublin) has resulted in a large number of experimental and theoretical papers aimed at an integrative analysis of cell signaling. This marriage between experimental and computational analysis of the receptor tyrosine kinase signaling network also drives much of his current studies to elucidate the deregulation of signaling crosstalk in diseases such as cancer and the implications for chemotherapy. In addition, the lab is carrying out a computational modeling analysis of the formation of reactive oxygen species (ROS) in the mitochondrial respiratory chain, which has identified features of hysteresis and bi-stability in mitochondrial ROS formation that may have implications for the response to transient hypoxia.
Dr. Hoek has received national and international recognition for his work on alcohol metabolism and its impact on disease. He is the recipient of the 2009 Mark Keller Award and Honorary Lectureship from NIAAA/NIH and the 2010 Henry Begleiter Award for Excellence in Alcohol Research from the Research Society on Alcoholism (RSA). Dr. Hoek is Associate Editor for Reviews and Commentaries of Alcoholism, Clinical and Experimental Research (ACER), the flagship journal for alcohol research. Dr. Hoek receives research grant support from NIAAA/NIH and is the program director for an NIAAA-supported Institutional Training grant (T32) that is currently in its 26th year of support at Jefferson. In addition, he is the recipient of a Senior Scientist Research and Mentoring Award (K05) from NIAAA/NIH.
Raj Vadigepalli, PhD
Dr. Vadigepalli is a Professor of Pathology, Cell Biology and Anatomy at Thomas Jefferson University. He also holds an Adjunct Professor position in Chemical Engineering at the University of Delaware. He received his Bachelors in Chemical Engineering from the Indian Institute of Technology in Madras, India, in 1996; his PhD in Chemical Engineering from the University of Delaware in 2001, with Specialization in Systems and Control Engineering; and his postdoctoral training in Bioinformatics at Thomas Jefferson University.
Work in Dr. Vadigepalli’s lab is directed at understanding the operational principles of mammalian tissue plasticity, renewal, repair and regeneration. A key goal is to develop novel clinical interventions and decision-support systems for regenerative medicine. They are focused on unraveling the landscape of cell phenotypes that is shaped by the underlying regulatory networks. The driving postulate is that variability of gene expression across cell types in functioning tissues is dysregulated as an adaptive mechanism in chronic disease as well as during development and regeneration. His lab employs a transdisciplinary systems' biology strategy that integrates computational modeling, systems engineering, bioinformatics, functional genomics, high-dimensional data analysis, and single cell scale experimentation. Their recent focus has been on analyzing and modeling gene and miRNA regulatory networks from molecularly and spatially defined single cells acquired through laser capture microdissection. Ongoing collaborative projects focus on liver repair and regeneration, alcoholic liver disease, brainstem neuroinflammation and neuroimmune processes leading to hypertension, cell fate regulation underlying developmental defects, and network modeling of renewal and regeneration in multiple mammalian tissues.
Dr. Vadigepalli has co-authored a number of peer-reviewed journal and conference publications in Biology/Medicine, Computational Biology and Systems Engineering. He has served on multiple review panels for the NIH, NSF and Army Research Office, and his work has been continuously funded by multiple grants from NIH. He currently serves as a Co-lead for the Computational Neuroscience Working Group of the Multiscale Modeling Consortium led by the National Institute of Biomedical Imaging and Bioengineering and the Interagency Modeling and Analysis Group. He also serves on the Committee for Credible Practice for Modeling and Simulation in Healthcare.
Zoe Wang, PhD
My research interests are concentrated on geonomic and personalized medicine. I recently established the Pathology Translational Genomics Laboratory and serve as Scientific Director of the facility. We have developed the capabilities for performing whole genome profiling for the analysis of microDNA expression, DNA methylation, and DNA copy number changes by array comparative genomic hybridization using current microarray technology. The laboratory also has developed next generation sequencing technology using Roche 454 FLEX sequencer. Applications that are in progress include RNA seq, ChIP seq, genome mutation detection, and verification of DNA methylation with bisulfite conversion. I collaborate with basic scientists and clinicians to study molecular mechanisms of human diseases with an emphasis on the changes at the genomic level.