2022 Fiscal Year Research-status Report
ニューロメジンUと関連ペプチドによるデクレチン効果と糖尿病病態との関連の解析
| Project/Area Number |
22K06004
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| Research Institution | University of Miyazaki |
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Principal Investigator |
張 維東 宮崎大学, 医学部, 助教 (90753616)
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| Co-Investigator(Kenkyū-buntansha) |
中里 雅光 宮崎大学, フロンティア科学総合研究センター, 特別教授 (10180267)
イスラム エムデイーヌルル 宮崎大学, 医学部, 研究員 (10870149)
迫田 秀之 宮崎大学, 医学部, 准教授 (50376464)
中里 祐毅 宮崎大学, 医学部, 助教 (90885972)
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| Project Period (FY) |
2022-04-01 – 2025-03-31
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| Keywords | インスリン分泌 / 迷走神経 |
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| Outline of Annual Research Achievements |
1) NMU and its action via neuronal signaling
We previously reported that NMU produced in β cells suppressed GSIS and caused β-cell failure via NMUR1 and its downstream signaling Gαi/o proteins in an antocrine/paracrine manner. However, vagus nerve has recently been considered another pathway that engages in the regulation of pancreatic function, and we hypothesized that NMU could act as a decretin after its secretion from the gut. From our results, peripheral administration of NMU to mice increased the expression of the neuronal activation marker FOS in the vagus nodose ganglion (NG) and the nucleus tractus solitarius. NMU was upregulated in the ileum and NG after 24h fasting. NMUR1 was upregulated in the NG and pancreatic islets during fasting. NMUR2 in hypothalamic was downregulated by 24h fasting. Collectively, the intestinal tract that senses fasting increases the expression of NMU and transmits fasting information to the central nervous system via the vagus nerve. It was presumed that the hypothalamic sensitivity to NMU was reduced in the hypothalamus, and the anorexic effect of NMU was reduced. In response to fasting, the changes are considered to promote appetite, prevent hypoglycemia from suppressing insulin secretion, and maintain the homeostasis of the body.
2) NURP expression and its insulinostatic effect.
NMU precursor-related peptide (NURP) is produced from the same precursor of NMU, but we confirmed that it expressed in pancreatic α cells and suppressed GSIS in β cells. Furthermore, NURP suppressed calcium influx and induced mitochondrial dysfunction.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
To investigate whether NMU regulates pancreatic function via vagal signaling, we have finished several experimental settings and all the experiments are going well as shown below.
1) Electrophysiology is the branch of neuroscience that explores the electrical activity of living neurons and helps to investigate the molecular and cellular processes that govern their signaling. We found that NMU increased the expression of the neuronal activation marker FOS in the vagus NG in mice, and we established an electrophysiological activity model by rats to investigate peripheral NMU effect on vagal afferents, and now we are increasing number of animals to confirm its activation on vagal afferents of pancreatic celiac branch and sympathetic efferents to pancreas.
2) Upon stimulation, the activated neurons can be traced by a marker of c-fos protein. NG is a sensory ganglion that conveys the peripheral signals to the brain. After peripheral NMU administration, we collected both nodose ganglions and brain to investigate the activated neurons and their localizations. In addition, we also use Cholera toxin subunit B, a highly sensitive retrograde neuroanatomical tracer, to investigate the subpopulation of NG neurons that innervate signals from peripheral organs including intestine and stomach.
3)NURP is a newly identified peptide from preproNMU. From our recent study, it may also be involved in the regulation of energy homeostasis and insulin secretion.To proceed the NURP research on pancreatic function, we are organizing a collaborative work on human study with groups in French and Bahrain.
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| Strategy for Future Research Activity |
1)To proceed the NMU effect on neuronal signaling, we will analyze the sybpopulation of activated neurons in NG that govern the stomach and intestine. And the blockade of vagal signaling will be performed to confirm the insulinostatic effect of NMU.
2)To proceed the NURP research on pancreatic function, we are working with a collaborative work with a French group (European Genomic Institute for Diabetes, University Hospital Lille), and a Bahrain group (Royal College of Surgeons in Ireland-Bahrain), to investigate the NURP effects on insulin secretion and β-cell function in humans. The agreement and collaboration has been confirmed and the further international joint research will start soon.
3)To investigate the NMU and NURP effects on energy expenditure, we are planning to administer these peptides chronically to mice using micro-osmotic pump, and the setting of Oxymax metabolic chamber is ready now. We are also performing glucose tolerance test in mice to confirm the optimal dose of NURP in the future experiments, and NURP on insulin sensitivity and gluconeogenesis will be studied.
4) Further studies are needed to identify the molecular mechanisms underlying the insulinostatic action mediated by NURP cognate receptor in β cells, and functional interactions between NMU and NURP. We are planning to identify the receptor of NURP using TriCEPS technique or GPCR screening, and now this research is under preparation. In addition, the NURP's possible role in regulating mitochondrial function and oxidative stress will also be investigated.
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