The long-term objective of our research is to elucidate the cellular and molecular mechanisms whereby arsenic, a toxic metalloid, increases the incidence of cancer, atherosclerotic and cardiovascular disease, reproductive and developmental problems and type 2 diabetes mellitus. Our overarching hypothesis is that very low, environmentally relevant, levels of arsenic dysregulates the expression of the serum glucocorticoid kinase (SGK1), which is over expressed in many cancers, most notably breast cancer. Moreover dysregulation of SGK1 has also been implicated in Parkinson's Disease, Huntington's Disease, diabetes, hypertension and obesity. In preliminary studies we made the novel observation that arsenic reduces SGK1 expression and thereby activates the ubiquitin-lysosomal mediated degradation of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel that regulates salt homeostasis in euryhaline teleosts (e.g. salmon and killifish), and in human airway epithelia cells. In this application studies will focus on elucidating the cellular and molecular mechanisms whereby arsenic dysregulates the expression and function of SGK1 and CFTR. In particular, studies will be conducted to test the hypothesis that arsenic is an endocrine disrupter and inhibits the transcriptional activation of SGK1 by disrupting cortisol-glucocorticoid receptor signaling. In addition, studies will also be conducted to elucidate how SGK1 regulates the ubiquitin-lysosomal pathway. Accordingly, studies will be conducted to test the hypothesis that SGK1 down-regulates the ubiquitin-lysosomal pathway by inhibiting Nedd 4-2, a ubiquitin E3 ligase that selectively ubiquitinates proteins such as CFTR and targets them for degradation in the lysosome. Studies will be conducted using three model systems: Fundulus heteroclitus (killifish), an environmental sentinel organism, Xenopus oocytes, a model system used extensively to study the regulation of ion channels including CFTR, and polarized human airway epithelial cells (CFBE). These studies will significantly increase our understanding of the molecular mechanisms whereby very low levels of arsenic disrupt SGK1 gene expression and function and the ubiquitin-lysosomal pathway, as well as elucidate the cell and molecular mechanisms whereby arsenic and SGK1 may contribute to breast cancer, Parkinson's Disease, Huntington's Disease, type 2 diabetes, hypertension and obesity.
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