The long-term objective of our research is to elucidate the cellular and molecular mechanisms wherebyarsenic, 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 thatvery low, environmentally relevant, levels of arsenic dysregulates the expression of the serum glucocorticoidkinase (SGK1), which is over expressed in many cancers, most notably breast cancer. Moreoverdysregulation 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 SGK1expression and thereby activates the ubiquitin-lysosomal mediated degradation of the cystic fibrosistransmembrane conductance regulator (CFTR), a chloride ion channel that regulates salt homeostasis ineuryhaline teleosts (e.g. salmon and killifish), and in human airway epithelia cells. In this application studieswill focus on elucidating the cellular and molecular mechanisms whereby arsenic dysregulates theexpression and function of SGK1 and CFTR. In particular, studies will be conducted to test the hypothesisthat arsenic is an endocrine disrupter and inhibits the transcriptional activation of SGK1 by disruptingcortisol-glucocorticoid receptor signaling. In addition, studies will also be conducted to elucidate how SGK1regulates the ubiquitin-lysosomal pathway. Accordingly, studies will be conducted to test the hypothesis thatSGK1 down-regulates the ubiquitin-lysosomal pathway by inhibiting Nedd 4-2, a ubiquitin E3 ligase thatselectively ubiquitinates proteins such as CFTR and targets them for degradation in the lysosome. Studieswill be conducted using three model systems: Fundulus heteroclitus (killifish), an environmental sentinelorganism, Xenopus oocytes, a model system used extensively to study the regulation of ion channelsincluding CFTR, and polarized human airway epithelial cells (CFBE). These studies will significantly increaseour understanding of the molecular mechanisms whereby very low levels of arsenic disrupt SGK1 geneexpression and function and the ubiquitin-lysosomal pathway, as well as elucidate the cell and molecularmechanisms whereby arsenic and SGK1 may contribute to breast cancer, Parkinson's Disease, Huntington'sDisease, type 2 diabetes, hypertension and obesity.
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