The overall goal of the research in the Conzen laboratory is to identify genetic and molecular mechanisms of mammalian stress signaling that contribute to both normal human physiology and disease. Glucocorticoids, a major mediator of the stress response, provide an excellent model for studying fundamental aspects of stress circuitry. In 2000, our laboratory identified glucocorticoid receptor (GR)-initiated signaling as a novel molecular mechanism for inhibiting breast epithelial cell apoptosis. Previously, glucocorticoids had been predominantly associated with inducing lymphocyte death, anti-inflammatory signaling, and homeostatic energy adjustment. These observations, and those of other laboratories, have revealed a novel connection between the physiological stress response and mechanisms of epithelial survival, thereby providing a link between the anti-inflammatory effects of the stress response and mechanisms of tissue protection.
Currently, we are using a variety of approaches including systems and traditional molecular biology as well has human genetic approaches to uncover the fundamental pathways and fine-tuning mechanisms of glucocorticoid-mediated cell signaling. For example, we created a Dynamic Bayesian Network algorithm for analyzing time-course gene expression data that allows a systems level identification of gene-gene relationships following GR activation. Secondly, to begin to understand the glucocorticoid-mediated stress response in a physiological context, we have developed animal models employing environmental stressors (e.g. social isolation) that result in altered neuroendocrine responses, and are associated with altered epithelial cancer cell gene expression and tumor growth. Finally, we have an ongoing collaboration using geography/climate-based population genetics to examine variations in non-coding regions that modulate the transcriptional response of stress-induced GR target genes. Our ultimate goal is to develop an integrated understanding of the stress response that includes gene expression at the cellular level, individual physiology, and population genetics.