Mechanism of Selenoprotein Synthesis

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DESCRIPTION (provided by applicant): Selenium is an essential trace element long known for its antioxidant properties, most or all of which are attributable to selenoproteins. Selenoproteins function in all aspects of life, from early development through diseases associated with aging, and most of the biological processes in between. Considerable progress has been made in our understanding of how selenium is incorporated into selenoproteins, but major gaps in our knowledge remain, including how selenium is preferentially retained and utilized in crucial tissues when the trace element is limiting. Likewise, the mechanisms dictating preferential synthesis of some selenoproteins over others when selenium is deficient remain enigmatic. Selenocysteine is recycled in the body via selenocysteine lyase, and our knowledge about the role of this enzyme in selenium supply is minimal. The overall objectives of this proposal are to elucidate the role of selenocysteine lyase in contributing to the hierarchy of selenoprotein synthesis, and to investigate the contributions of selenocysteine lyase when selenium transport is impaired due to selenoprotein P knockout. The long-term goals of our research are to understand the underlying molecular, cellular and tissue-specific mechanisms behind the regulatory pathways governing selenium distribution and selenoprotein synthesis. Achievement of these goals will provide information that is essential to furthering our understanding of how selenium is utilized for optimum health. Our central hypothesis is that selenocysteine lyase functions in tissue- and selenoprotein-specific recycling of selenocysteine, contributing to mechanisms whereby the most crucial tissues and selenoproteins have priority on selenium when the trace element is limiting. Our central hypothesis will be tested via the following specific aims: 1) characterize the effects of selenocysteine lyase knockout on tissue selenoprotein mRNA and protein expression, and effects on anatomy, physiology, histopathology, neuromotor function and neurobehavior; 2) generate combined selenocysteine lyase- selenoprotein P knockout mice, and characterize as described for aim 1; and 3) characterize mRNPs associated with selenoprotein mRNAs that are either preserved or targeted for degradation under the conditions in aims 1 and 2. These studies will provide new insights into the mechanisms of selenium distribution, selenoprotein synthesis, and circumventing nonsense-mediated decay of selenoprotein mRNAs.