Thyroid hormones are essential for coordinated fetal and neonatal growth and development, as well as metabolic, reproductive and cardiovascular functions throughout life. The diverse physiological effects of thyroid hormones are mediated through cellular events that may be initiated within the cell nucleus, the plasma membrane, the mitochondrion and the cytoplasm. The overall goal of the research program in the Carr lab is to understand the cellular events which mediate thyroid hormone action in development and pathophysiology, thyroid cancer.
Environmental toxins, by disrupting endocrine function, have emerged as a major public health issue. Endocrine disrupting chemicals with structural similarities to steroid and thyroid hormones have been shown to mimic or antagonize hormone action at the cellular level resulting in disruption of a complex array of genomic and non-genomic events resulting in discordant reproductive development, impaired neurodevelopment, disruption of thyroid homeostasis and an increase in endocrine-related cancers. The goals or our endocrine disruption program in environmental carcinogenesis are to 1) determine the intracellular mechanism(s) of disruption of thyroid hormone action in pituitary and thyroid tumor cells and 2) elucidate the impact on the etiology of thyroid cancer in tumor cells and tumor biomarkers in thyroid cancer clinical studies. To determine the impact of selected toxins on thyroid hormone mediated cellular processes, the laboratory uses a variety of biochemical, molecular, proteomic, and microarray techniques. Our recent studies in pituitary tumor cells revealed that bisphenol A (BPA) and DDE, a metabolite of the pesticide DDT, in part through disruption of the thyroid hormone receptor (TR) within the nucleus, alter cell proliferation as well as gene expression (Zakrzewska et al. 2010). Through proteomic analysis and expression arrays, we are determining the functional significance of toxin disruption of the nuclear protein complex assembly with the thyroid hormone receptor (TR) that mediates thyroid hormone effects on gene regulation. We are also determining whether selected toxins alter plasma membrane (integrin) mediated changes in intracellular signaling including MAPK, PI3K phosphorylation of the TR to induce a cellular mislocation of the TR to impede gene regulation and tumor suppression as detected by IF and confocal microscopy. We have recently characterized the molecular phenotypes of benign thyroid cells and differentiated and de-differentiated thyroid cancers (Zakrzewska et al. 2008). The lab is determining the impact of selected environmental toxins on selected biomarkers, cell motility, cell invasion and microRNA profiles in human thyroid cancer cell lines and thyroid tumors.
Last modified November 24 2014 10:10 AM