生物谷报道：根据发表在7月10日的刊物《生物化学杂志》（Journal of Biological Chemistry）上的结果，人体制造胰岛素的能力或许可以通过抑制一种新发现的分子而得到提高，从而帮助治疗糖尿病。
这一分子被称为miR124，它是一种microRNA分子，由伦敦帝国学院和法国INSERM U145及EMI 0363的科学家共同发现。研究小组认为，miR124阻碍了胰脏中胰岛素的生成。它通过控制分泌胰岛素的β细胞的多个基因而实现这一点。
胰岛素负责控制体内血糖浓度，一旦胰岛素不足，就会导致糖尿病。因此科学家相信，如果找到抑制miR124或者其它相关的microRNA的药物，就可以保证身体产生更多的胰岛素，从而帮助对抗糖尿病。DNA通过RNA将基因信息转化为蛋白质，而microRNA结合到特定信使RNA上，阻止翻译过程的发生。它们阻碍蛋白质的合成然后干扰细胞的正常活动。某些合成分子可以关闭microRNA的活动，因此科学家希望可以驾驭它们的这一特性来关闭某些microRNA，包括miR124。小组同时期望了解，在编码miR124的基因中存在的多态现象是否使得某些人更容易患上糖尿病。
来自伦敦帝国学院医学系得Guy Rutter教授是此项研究的作者之一，他表示：“科学家们仅仅在数年前才发现microRNA的重要性。而发现这一特定的microRNA在控制胰岛素产生过程中起着基本作用是令人兴奋的，这将帮助我们找到治疗糖尿病的新工具，目前糖尿病影响着5%的人群，并且其发生率正在逐年上升。”此项研究得到了多个研究机构的支持。
FIGURE 1.
Specific expression of microRNA-124a in mouse tissues. A, primer sequences to miR-124a isoforms. The sequences of the precursor and mature members of the mouse miR-124a family of isoforms are shown. Underlined, sequences of the mature miRNA-124a. F and R, sequences of the forward/reverse PCR primers amplifying miR-124a (corresponding to a 60 bp); F' and R', sequences of the forward/reverse PCR primers amplifying the miR-124a2-specific isoform (corresponding to a 105 bp); in bold, sequences that differ among isoforms. Sequences are presented in the 5' to 3' direction. B, RT-PCR of mouse total tissues and -pancreatic models. Representative abundance of miR-124a2 (upper panel) and miR-124a (lower panel) and corresponding U6 small nuclear RNA in tissue. Br, brain; Ht, heart; Lg, lung; Lv, liver; Pn, pancreas; Kd, kidney; Sp, spleen; Ms, muscle; Min-6, mouse insulinoma -cells; Ins-1E, rat -pancreatic cells; Islet, mouse pancreatic islets. C, microRNA-124a expression levels at stage e14.5 and e18.5 in developing pancreas of mouse embryos. The results are expressed as relative units normalized with tRNA and are the mean ± S.D. from 3 samples. **, p < 0.01.
原文出处：
MECHANISMS OF SIGNAL TRANSDUCTION:
Nadine Baroukh, Magalie A. Ravier, Merewyn K. Loder, Elaine V. Hill, Ali Bounacer, Raphaël Scharfmann, Guy A. Rutter, and Emmanuel Van Obberghen
MicroRNA-124a Regulates Foxa2 Expression and Intracellular Signaling in Pancreatic -Cell Lines
J. Biol. Chem., Jul 2007; 282: 19575 - 19588 ; doi:10.1074/jbc.M611841200
Abstract Full Text PDF Purchase Article View Shopping Cart Supplemental Data
Mirn124a-2
Official Symbol Mirn124a-2 and Name: microRNA 124a-2 [Mus musculus]
Other Aliases: mir-124a-2
Chromosome: 3; Location: 3
GeneID: 723950
作者简介：
Professor Guy Rutter
Molecular aspects of glucose sensing by pancreatic islet beta cells and hypothalamic neurones
Department of Biochemistry
G.A.Rutter@bristol.ac.uk
Projects - Diseases - Processes - Techniques - Equipment - Funding - Collaborations - Teaching - Group members - Publications & further information
Research
Guy Rutter has recently left Bristol to take up the Chair in Cell Biology and Head of Cell Biology at Imperial College London.
Recognising nutrients is a fundamental problem for all living cells. For simple organisms, such as bacteria and yeast, it's a question of life and death.
In complex animals, including mammals, the job of sensing changes in nutrient concentration in the blood is performed by highly specialised cell types. Beta-Cells of the pancreatic islets of Langerhans, which secrete insulin when blood glucose rises, are particularly important: defective insulin release causes non-insulin-dependent diabetes mellitus (NIDDM). Exposure of islet Beta cells to high glucose concentrations activates a number of signalling pathways, leading to activated gene expression and the exocytosis of insulin.
I am interested in dissecting the mechanisms whereby these crucial cells sense glucose and the signal transduction pathways that allow them to control insulin release. Making use of the MRC Cell Imaging Facility, in whose inception I was closely involved, my research is based on the analysis of signalling pathways in single living cells. This involves developing the use of bioluminescent and fluorescent probes. Combining the use of these probes with microinjection and adenovirus transfection, we are able to turn a living cell into a miniature test tube. An essentially infinite variety of molecules can then be introduced.
My interest in neuroscience stems from studying the mechanisms of exo- and endocytosis, which is responsible both for the release of insulin and of neurotransmitter at the chemical synpase. Pancreatic Beta cells are an ideal system to study exo- and endocytosis. Neurones store synaptic vesicles in synaptic terminals which are many times smaller than Beta cells, and hence it is hard to measure or manipulate events experimentally. The general principles of vesicle cycling can therefore established in secretory Beta cells, and then be applied to the release and recyling of synaptic vesicles.
Membrane recovery following neurotransmitter release is a highly controversial issue. I have investigated one of the endocytotic mechanisms proposed, 'Kiss and Run', using evanescent wave microscopy (or TIRFM, Total Internal Reflection Fluorescence Microscopy).
Another area of my research that extends into neuroscience is the characterisation of hypothalamic neurones. We have found that in these cells, changes in glucose levels gives rise to ATP 'microdomains' within the cell. We are investigating the role of microdomains using ultra-low light level imaging and electrophysiological methods.
Current projects include:
Insulin and other gene expression, including a variety of transcription factors, in single living islet cells. Characterising signalling pathways, including phosphatidyl inositol 3-kinase and AMP-activated protein kinase. Activation of insulin trafficking and release using of a combination of recombinant fluorescent probes (GFP), confocal and near-field imaging to monitor the flow of secretory proteins through the cell. The role of Ca2+ in mobilizing intracellular secretory vesicles using evanescent wave / total internal reflection fluorescence. The role of mitochondrial metabolism, and intracellular ATP concentration, in prompting insulin secretion; ultra-low light luminescence detection (Patent in preparation) to study 'microdomains' of intracellular ATP concentration within single living beta cells and also in hypothalamic neurones. These changes in ATP are blocked by over-expression of the enzyme lactate dehydrogenase, which is essentially lacking from the islet cell, suggesting that over-expression of this enzyme leads to diabetes. The role of intracellular Ca2+ microdomains. We have demonstrated compartmentalisation of intracellular Ca2+ concentration and shown a role for Ca2+ in changing in mitochondrial oxidative activity.
Possible future projects and direction of research:
We are increasingly combinining molecular techniques with the use of transgenic models.
Diseases related to this field of research
Diabetes
Processes and functions relevant to this work
Energy homeostasis, mammalian metabolism, exocytosis, endocytosis, vesicle cycling, secretion, intracellular signalling
Techniques in routine use
Confocal microcsopy, adenoviral vector construction, islet and hypothalamic islet isolation and culture, routine biochemistry and molecular biology, ATP imaging, electrophysiology, evanescent wave microscopy, Total Internal Reflection Fluorescence Microscopy, (TIRFM)
Equipment in routine use
Confocal microscope, TIRF imaging system, ultralow light level imaging camera, electrophysiology rig (HEKA)
Publications, recommended reading and further information
Walker, S.A., Kupzig, S., Wheeler, L.C., Tsuboi, T., Lockyer, P.J., Bivona, T., Cozier, G.E., Buckler, A., Rutter, G.A., Allen, M., Philips, M.R., Cullen, P.J. (2004)
Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca(2+) oscillations.
EMBO J, 23(8): 1749-60.
Tsuboi T, McMahon HT, Rutter GA.
Mechanisms of dense core vesicle recapture following "kiss and run" ("cavicapture") exocytosis in insulin-secreting cells.
J Biol Chem. 2004 Nov 5;279(45):47115-24. Epub 2004 Aug 25.
Rutter, GA, 2001
Mol Aspects Med. Dec;22(6):247-84.
Nutrient-secretion coupling in the pancreatic islet beta-cell: recent advances
Ainscow, E.K., Mirshamsi, S, Tang, T., Ashford, M.L., and Rutter, G.A, 2002
J. Physiol, 544.2, 429-445
Dynamic imaging of free cytosolic ATP concentration during fuel sensing by hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels
