The function of the imprinted microRNA-483 in growth, metabolism and cancer

印迹microRNA-483在生长、代谢和癌症中的功能

• 批准号: MR/J001562/1
• 负责人: Miguel Constancia
• 金额: $ 60.35万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ001562%2F1
• 关键词: function; imprinted; microRNA; 483; growth

MicroRNAs are small molecules that control the amount of proteins that the body makes, as well as the timing that these proteins are made. Because of this action they are very important for development and the health of organisms. The precise function of many microRNAs, estimated to be in their hundreds in humans, is unknown. Many of these small molecules are made from inside genes and they are dependent on those genes machinery to be produced. MiR-483 is a microRNA that is produced by the machinery that makes an important growth factor in the body called Igf2. We know what Igf2 does, it promotes growth and is also involved in how much fat and sugar we can store, but nothing is known about its partner microRNA. We have made an interesting observation: when we make a mouse that does not have the microRNA, but still makes the growth factor Igf2 normally, this results in postnatal overgrowth (the genetically engineered mice are about 10% heavier than their brothers and sisters that were not engineered). This exciting results suggests that the main function of this microRNA is to put the brakes on growth, a function that is precisely the opposite of its host gene! We now want to find out more about this microRNA - what else does it do in addition to regulate postnatal growth? Is it involved in the many ways we control fat and sugar storage and how we use those stores? Does it have a role in diseases of growth such as cancer? What genes and proteins does this microRNA help to control? Can we find precisely how it works? This project is important because it can give us new clues on how microRNAs work, in particular in growth control (as far as we know this is the first example of an microRNA involved in control of body size). If it turns out that its normal function is indeed to put down the brakes on growth it will be very important to consider using it as an anti-cancer therapy. Other diseases of growth control, such as those that lead to smaller babies and big babies, with and without postnatal growth compensation may also benefit from our research.

MicroRNAs是一种小分子，它控制人体合成蛋白质的数量，以及这些蛋白质的合成时间。由于这一作用，它们对生物体的发展和健康非常重要。许多微小RNA的确切功能尚不清楚，据估计，在人类中有数百个。这些小分子中的许多都是由内部基因构成的，它们依赖于这些基因的机制来产生。MIR-483是一种微小RNA，由体内一种名为Igf2的重要生长因子的机械产生。我们知道Igf2是做什么的，它促进生长，还与我们可以储存多少脂肪和糖有关，但对它的伴侣microRNA一无所知。我们做了一个有趣的观察：当我们制造一只没有microRNA的小鼠，但仍然正常地产生生长因子Igf2时，这会导致出生后的过度生长(转基因小鼠比它们的兄弟姐妹重约10%)。这一令人兴奋的结果表明，这种微小RNA的主要功能是阻止生长，而这一功能恰恰与其宿主基因相反！我们现在想了解更多关于这种微小RNA的情况--除了调节出生后的生长，它还能做什么？它与我们控制脂肪和糖储存的许多方式以及我们如何使用这些储存有关吗？它在癌症等增生性疾病中有作用吗？这种微小的RNA有助于控制哪些基因和蛋白质？我们能准确地找到它是如何工作的吗？这个项目很重要，因为它可以为我们提供关于microRNA如何工作的新线索，特别是在生长控制方面(据我们所知，这是microRNA参与控制身体大小的第一个例子)。如果事实证明，它的正常功能确实是抑制增长，那么考虑将其用作抗癌疗法将是非常重要的。其他生长控制疾病，如那些导致较小婴儿和较大婴儿的疾病，无论是否有出生后生长补偿，也可能从我们的研究中受益。

项目成果

Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.

• DOI: 10.1371/journal.pgen.1009069
• 发表时间: 2020-10
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Hammerle CM;Sandovici I;Brierley GV;Smith NM;Zimmer WE;Zvetkova I;Prosser HM;Sekita Y;Lam BYH;Ma M;Cooper WN;Vidal-Puig A;Ozanne SE;Medina-Gómez G;Constância M
• 通讯作者: Constância M

Intergenerational epigenetic inheritance in models of developmental programming of adult disease.

• DOI: 10.1016/j.semcdb.2015.06.006
• 发表时间: 2015-07
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Fernandez-Twinn DS;Constância M;Ozanne SE
• 通讯作者: Ozanne SE

Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p'-DDE

脂肪组织功能障碍是导致长期接触对,对-DDE 引发代谢障碍性肥胖的核心机制

• DOI: 10.17863/cam.12928
• 发表时间: 2017
• 作者: Pestana D

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

• DOI: 10.1101/2022.09.09.507324
• 发表时间: 2022-09
• 期刊: bioRxiv
• 作者: I. Sandovici;D. Fernandez‐Twinn;Niamh Campbell;W. Cooper;Y. Sekita;I. Zvetkova;D. Ferland-McCollough;H. Prosser;L. Oyama;D. Cimadomo;Karina Barbosa de Queiroz;Cecilia S.K. Cheuk;Nicola M. Smith;R. Kay;Katharina Hoelle;N. H. Smith;S. Geyer;L. Reissig;W. Weninger;K. Siddle;A. Willis;M. Bushell;S. Ozanne;M. Constância

Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis

• DOI: 10.1101/2023.06.27.546683
• 发表时间: 2023-07
• 期刊: bioRxiv
• 作者: I. Sandovici;Borbála Mifsud;A. Emery;P. Gulati;K. Kentistou;A. Banu;Niamh Campbell;B. Hardwick