This application requests support for an outstanding junior faculty through a Research Supplement to Promote Diversity in Health-Related Research. The parent grant for this Administrative Supplement application proposes to provide new insights into the mechanisms of Se distribution and the functions of Se recycling, with an overall goal of elucidating pathways and mechanisms underlying the development of diet-induced obesity in the Scly KO mice. A particular topic to be investigated in the Specific Aim 3 is the effect of Scly-dependent genes in hepatocytes, their relationship with Se metabolism, and overall impact on energy metabolism in a sex-dependent manner. This specific topic will be the focus of this Research Plan, particularly the relationship between Scly and Se-binding protein 2 (Selenbp2), a Se-dependent protein candidate uncovered by RNA-Sequencing analysis in hepatocytes. The proposed studies will establish whether Selenbp2 is a functional partner of Scly and the impact of this relationship on amino acid pathways, particularly glycine and alanine, as our most recent publication unveiled these pathways as the most affected in livers of Scly KO mice. Moreover, this research plan will examine whether Se levels modulate this relationship and its metabolic consequences in obese male and female Scly KO mice. Hence, the objective of this research plan is to characterize the relationship between Se-dependent factors Selenbp2 and Scly in vitro and in vivo. To achieve this goal, Dr. Seale will utilize PLA assays, cell lines where Selenbp2 or Scly will be edited using CRISPR-Cas9 technology, and primary hepatocytes from Scly KO mice. These tools will demonstrate whether Scly and Selenbp2 are functionally associated and will complement the experimental design laid out in the parent grant. As Scly is inversely regulated by Se levels, this study will also determine the molecular mechanism of Se regulation of Selenbp2 in obese mice. The accomplishment of this research will provide the basis for future projects detailing the molecular mechanisms of Se distribution in cells as well as future projects evaluating the impact of Se recycling in human populations afflicted by obesity. In addition to these important scientific contributions she will make, the proposal describes acquisition of new research skills and knowledge to broaden her expertise, including experience in community-based participatory research, and a comprehensive career development plan incorporating training in grantsmanship, leadership, mentoring and increased proficiency in oral communication. This supplement will be extremely valuable in promoting the candidate?s career and professional development towards independence, while also increasing diversity at the University of Hawaii.
Selenium is an essential nutrient with a narrow range for health benefits ? either too little or too much is detrimental. We are investigating selenium metabolism, which is handled differently in males and females, and the detrimental public health effects due to disruptions in selenium metabolism. !
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