| Project/Area Number |
22K06004
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 42020:Veterinary medical science-related
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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, 特別講師 (90753616)
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| Co-Investigator(Kenkyū-buntansha) |
中里 雅光 宮崎大学, 医学部, 研究員 (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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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2024: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | インスリン分泌 / 迷走神経 / ペプチド / 受容体 / インスリン |
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| Outline of Research at the Start |
本申請では、ニューロメジンU (NMU)のデクレチン効果の分子機序を明らかにし、神経を介する消化管と膵臓の新たな臓器連関を呈示する。糖尿病や肥満では膵β細胞障害が起こる。NMUの糖尿病や肥満の病態との関連を解析することが、２番目の主題である。NMUと同じ前駆体蛋白質から産生される neuromedin U precursor-related peptide (NURP) が共同研究者により同定された。本申請の3番目の主題は、NURPが膵β細胞機能に与える作用を解析し、1つの前駆体から2つの生理活性ペプチドが産生される生物学的意義ならびに糖尿病や肥満における病態生理学的意義を明らかにしたい。
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| Outline of Annual Research Achievements |
1) Insulinostatic effect of NMU via neuronal signaling. We have previously confirmed that NMU activates vagal afferents. Recently, we further confirmed that blockade of vagal afferents (capsaicin-induced vagal injury) abolished the insulinostatic effect of NMU, and interestingly, peripheral NMU also increased the activity of the greater splanchnic nerve, further supporting the potential of NMU in neural activity. The NG is a sensory ganglion that transmits peripheral signals to the brain. We found that peripheral administration of NMU increased the expression of the neuronal activation marker FOS in the PVN but not in the ARC in mice, suggesting that PVN neurons are responsible for NMU signalling.
2) Metabolic effects of preproNMU-derived NMU-related peptide (NURP). To investigate the metabolic effects of NURP, we continuously administered either NMU or NURP to mice for 1 week by using a micro-osmotic pump, and found that NURP increased heat production, locomotor activity and oxygen consumption. In addition, unlike NMU, NURP slightly increased food access and food intake of mice.
3) NURP has effect on human islets and acts via its respective receptors. With the support of collaborative groups in France and Bahrain, we identified that NURP suppressed GSIS in both human islets and β-cells. To identify the molecular mechanisms underlying the insulinostatic action mediated by NURP cognate receptor in β-cells, and to advance the NURP research on pancreatic function, we identified some candidate of receptors (MRGPR family protein) of NURP using GPCR screening technique.
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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
1) To investigate the role of decretin in the regulation of pancreatic function, we have completed the study of the effects of NMU on both vagal afferents and sympathetic nerves. Taken together, peripheral administration of NMU activates the electrical activity of vagal afferents and SNS efferents, which may be responsible for the suppression of insulin secretion. The expression levels of NMU and Nmur1 increased in the small intestine, vagus nerve neurons and pancreatic islets during fasting. In addition, NMU became more sensitive and suppressed insulin secretion during fasting. Conversely, the expression level of Nmur2, which is expressed in the central nervous system, decreased during fasting. Since central NMU inhibits feeding, it makes sense that its receptors would decrease during fasting. In this way, NMU suppresses insulin secretion to maintain blood glucose levels during fasting, and the reduction in Nmur2 prevents the central suppressive effect of NMU from increasing. The expression levels and regulatory mechanisms of the two types of NMU receptors differ between organs.
2) NURP is a newly identified peptide from preproNMU. Our recent study verified that this peptide was involved in the regulation of energy homeostasis and insulin secretion, and also identified its candidate receptors. To advance the NURP research on pancreatic function, we investigated the effects of NURP on insulin secretion and β-cell function in humans. Both the batch assay in human β-cells and the perifusion assay in human islets confirmed that NURP is involved in insulin secretion.
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| Strategy for Future Research Activity |
1) The suppressive effect of NURP on GSIS has been confirmed in vitro, but in vivo GTT experiments, NURP has no effect on GSIS, the experimental protocol should be modified (e.g. dose of the peptide, route of administration, time interval, peptide degradation time) to confirm its effects, and we are also investigating insulin sensitivity and gluconeogenesis in the near future, to help provide more information for further therapeutic development.
2) The effect of NURP on GSIS has been demonstrated in human pancreatic islets, the repeated experiments and sample number are needed to confirm this conclusion, in both male and female humans.
3) We have identified the candidate of NURP cognate receptors in β-cells,further studies are needed to identify the molecular mechanisms underlying the insulinostatic action mediated by these candidate receptors, and functional interactions between NMU and NURP. In addition, in combination with the knockdown experiments of the candidate receptors, and by using the NURP ko animals, the NURP's possible role in the regulation of mitochondrial function and oxidative stress will also be investigated.
4) NMU and MURP are exist in β-cells and α-cells, although they are produced from the same precursor of NMU. By using the NMU and NURP ko animals, and the sequencing of these two peptides, we will confirm their exact localisation, which could help to investigate the mechanism (alternative splicing or not) of the production of these two peptides, to provide more information in peptide exploration and identification.
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