Jeremy Caldwell, Ph.D.
Director of Molecular and Cell Biology
Our basic research in cellular biology is testimony to both the cross-disciplinary nature of work at GNF and to the fact that we take advantage of the latest that technology has to offer—sometimes building that technology ourselves. Much of our research is viral- and cancer-related.
Viral pathogens have evolved unique solutions for their survival by co-opting host-cell biological processes and machinery. The focus of our research is the mechanisms by which RNA viruses exploit host-cell machinery to enter, integrate, express, and replicate their genomes. We are interested in how retroviruses like murine leukemia virus (MLV), human immunodeficiency virus (HIV), and flaviviral species such as hepatitis C virus (HCV) become pathogenic.
We take a chemical genetic approach to identifying tools for disrupting viral pathways. Using our state-of-the-art high throughput small molecule and genetic screening technology, we can begin to probe host genomes using compound/cDNA/siRNA/shRNA screening, expression profiling, complementation, and two-hybrid analyses to identify critical cellular vehicles exploited by these viruses.
Unlike viruses, which acquire a survival advantage using host-cell factors, tumor cells survive and grow because of mutation to their own (host) genes. The precise molecular events that transform a normal cell into a cancerous one are currently being unraveled by the oncology research community.
In parallel efforts, we are focused on the identification of novel factors involved in growth and cell proliferative states of cancerous and non-cancerous cells. We apply small molecule and gene-based library screens to identify factors that uniquely perturb the growth phenotype of cancerous versus normal cells. We also exploit differences in global responses to active molecules and gene expression profiles to rapidly deconstruct response patterns and identify candidate effector genes. In these efforts, we explore the utility of high content imaging/screening methodologies to allow more comprehensive phenotypic analysis and optimized gene/compound mechanism of action to distinguish cell cycle requirements of novel glioblastoma and other cancer cell effectors.
Finally, a new strategy in the area of phenotypic HTS involves multidimensional data analysis in which data from parallel, independent screening experiments are rendered mathematically comparable for comprehensive analysis by data-mining. This emerging field allows correlation between activity patterns corresponding to a given compound or gene across a broad panel of cellular assays, which through hierarchical clustering, principal component analysis, and other algorithms allows functional assignment to these effectors.
Using GNF’s HTS database of 1.7 million compounds and more than 200 HTS assays by GNF’s uHTS system, we conduct comparative analysis between drugs of known function with unannotated compounds. This has generated hypotheses about the function of hundreds of compounds' mechanism of action. This strategy encompasses mechanisms of cell proliferation, but is unique in its incorporation of compound data specific to metabolic disorders, infectious disease, inflammation, cardiovascular processes, and other biomedically relevant areas.
Selected Publications
