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overview My laboratory performs Biomedical Research at the interface between genetics and the environment through investigations that find common ground in embryonic development and adult disease. We study master regulators (homeobox, PPAR/RXR and Ets family genes), whose activities control cell type specification or ‘fate decisions’ and are in turn controlled epigenetically by exposures to agents, including natural and anthropogenic endocrine disrupting compounds (EDCs). The increase in bulk and variety of anthropogenic EDCs appears to closely parallel a variety of human health issues, including cancer, obesity, inflammation/immunity, cardiovascular and neurological diseases. For this work, we have relied heavily on animal model and cell-based systems and have created tools that act as surrogates for studying genetic interactions and cell fate determination as they pertain to human health trajectories. Sophisticated transgenic, knockout and xenograft rodent mammalian models have shown us the roles of particular homeobox and Ets genes in thoracic/urogenital patterning and epithelial cell fate, especially related to breast, lung and prostate carcinogenesis. For example, we observe that common estrogenic/anti-androgenic contaminants profoundly alter homeobox expression patterns in the embryo and cancer cells and are pursuing an understanding of these exposures on long-term health. Also, Hox homeobox and Ets1 gene disruptions have shown us that genetic background (i.e. modifier loci) can profoundly change whether a loss or gain in gene function is embryonic lethal or produces a minimal phenotype, pushing us to view “one size fits all” diagnostics and/or therapeutics with caution. Thus, we seek to improve these models to go beyond the investigation of common biomolecular mechanisms to patient-specific ‘humanized’ models that bridge the gap from basic research to diagnosis, prognosis and treatment-based pre-clinical/clinical trials. Towards this end, we have developed a method for freezing freshly excised human tissues, such that when thawed these tissues behave as if freshly isolated (live cells and intact 3-D architecture). Currently, we are using these patient-derived tissues for improved xenograft animal and ex vivo organ culture models to develop diagnostics (e.g. molecular signatures in parent tumors that indicate metastatic potential) and therapeutics (e.g. cancer cell resistance testing in native 3-D microenvironments). We use human induced pluripotent stem cells (iPSCs) as surrogates for studying the impact of environmental agents on embryonic cell type determination. Most recently, we have used human iPSCs to show that a major component of COREXIT, the solution used to disperse the Gulf Oil Spill, is a potent ‘obesogen’ that drives stem cell fate towards adipogenesis at the expense of osteogenesis (via altered PPARg/RXRa activities). This is potentially quite important given that 1.2 million gallons of COREXIT were used in the Gulf for oil spill clean up and since the obesogenic component is widely used in household cleaning products. This underscores our need to realize that while we are excellent builders of tools to solve specific problems we are not yet at a level to understand the influences of our tools on complex system-based levels. In this work on gene-by-environmental interactions, we hope provide tools to test novel dispersants; new tools that go beyond organism/cell toxicity testing to cell fate testing in order to more fully understand their potential to perturb long-term health trajectories.
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  • Pluripotent Stem Cells