2017 Fiscal Year Annual Research Report
ヒ素による糖代謝異常における膵α細胞の役割に関する研究
| Project/Area Number |
16F16418
|
|---|
| Research Institution | Kobe University |
|---|
Principal Investigator |
清野 進 神戸大学, 医学研究科, 特命教授 (80236067)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
CARMEAN CHRISTOPHER 神戸大学, 医学(系)研究科(研究院), 外国人特別研究員
|
|---|
| Project Period (FY) |
2016-10-07 – 2019-03-31
|
| Keywords | Insulin Secretion / Diabetes / Endocrin Disruptors / Arsenic / Serotonin / Metabolomics / Gene Expression / Detoxification |
|---|
| Outline of Annual Research Achievements |
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.
|
| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
論文を投稿した。（2018年4月）
|
| Strategy for Future Research Activity |
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.
|
