| 研究実績の概要 |
RNA sequencing were performed on arsenic-exposed MIN6-K8 beta cells. Of the 4 genes that were significantly regulated during arsenic exposure and replicated in independent studies, three were evaluated further. Each gene was knocked down by siRNA. Two of these genes, Upk3a, and Ugt1a6a, appear to dramatically affect beta cell function during arsenic exposure. Interestingly, Ugt1a6a is a serotonin-targeting phase 2 detoxification enzyme. Our own parallel, unbiased metabolomics analysis determined that arsenic exposure reduced levels of beta cell 5-hydroxytryptophan, which is the rate-limiting precursor for serotonin synthesis. We found that supplementation with 5-hydroxytryptophan or knockdown of Ugt1a6a recovered beta cell function following arsenic exposure. We submitted a manuscript reporting these findings to a peer-reviewed journal recently.
We have recently completed the first phase of developing knockout beta cell lines lacking each of the genes mentioned above, Upk3a and Ugt1a6a. We are also now exploring the additional collaboration with a Japanese laboratory, to identify the chemical targets of Ugt1a6a, and we have begun arsenic exposure studies in human islets.
CMC has published one paper as 2nd author with our laboratory’s collaborator at the University of Illinois at Chicago, Chicago, IL, USA. CMC has submitted 1 manuscript as first-author for peer reviewed publication. CMC is currently preparing an invited review for publication in a peer-reviewed endocrinology-focused journal.. CMC has presented at 4 scientific meetings since May 1, 2017.
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| 今後の研究の推進方策 |
Plan for next 4 months:
We aim to complete the development of CRISPR-Cas9 knockout cell lines for two genes of interest, Ugt1a6a and Upk3a. Once validated, we will evaluate the phenotype and underlying mechanisms of action. We also aim to identify the specific target(s) of the phase 2 detoxification enzyme, Ugt1a6a, which has a strong phenotype in our beta cells. We anticipate completing a second manuscript focused largely on the action of Ugt1a6a in beta cells and islets.
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