Role of the imprinted Igf2 gene in pancreatic development and function

印记 Igf2 基因在胰腺发育和功能中的作用

• 批准号: BB/H003312/1
• 负责人: Miguel Constancia
• 金额: $ 51.99万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH003312%2F1
• 关键词: Role; imprinted; Igf2; gene; pancreatic

The pancreas is a large gland in the body with two very important functions: it makes insulin and digestive enzymes. The part of the pancreas which produces insulin and other hormones is called the endocrine pancreas. The part of the pancreas that produces the digestive enzymes is called the exocrine pancreas. Digestive enzymes break down food into small components allowing it to be easily absorbed from the intestine. Insulin is produced by specialized cells of the endocrine pancreas called beta cells. Insulin controls your sugar levels in the blood and makes sure that the body cells get enough energy and can store it for later use. The pancreas is able to 'sense' the level of sugar in the blood - if too high the beta cells make and secrete more insulin. If the level is too low, it secretes less. There are conditions when not only more insulin is needed but the number of beta cells needs to increase in order to cope with the increased demand for insulin. These circumstances include normal ageing, pregnancy and obesity to mention a few. Failure to increase the number of beta cells in the above conditions can lead to increased levels of sugar in the blood and diabetes. We know little about how the pancreas is able to increase the number of beta cells when needed. Consequently, to determine the factors that control this adaptive process is very important. The aim of this study is to determine precisely how a gene, that we think is a master regulator of pancreatic growth and function, actually works. This gene encodes for a protein that is similar to insulin - it is suggestively called insulin-like growth factor 2 (Igf2). We have preliminary evidence suggesting that Igf2 is an important factor that controls the normal development of the pancreas and makes beta cells multiply when needed. Many of our attempts to decipher mechanisms which are important for human health and disease both rely and benefit from studying animal models. In this study we will use mice because their pancreas is similar to the human one and because we can remove the Igf2 gene in their beta cells or in the entire pancreas, allowing us to understand how this gene works. We can also increase the amount of Igf2 produced by the beta cells or in the entire pancreas. We will study the development and the structure of the pancreas that can not make Igf2 or makes more Igf2 than normal mice. We will pay particular attention to the effect of the lack or excess of Igf2 on development of the pancreas and the number of beta cells during ageing. We will also study how changing the amount of Igf2 affects the way pancreas makes new beta cells during normal pregnancy, during exposure of mice to high-fat diet (to mimic human obesity) or when the pancreas is injured. We will use these experiments to find which other genes are under the control of Igf2. The results of this study will help to understand better how the pancreas develops, how it works during normal circumstances and how it adapts to conditions which increase the demand for insulin.

胰腺是体内的一个大腺体，具有两个非常重要的功能：产生胰岛素和消化酶。胰腺中产生胰岛素和其他激素的部分称为内分泌胰腺。胰腺中产生消化酶的部分称为外分泌胰腺。消化酶将食物分解成小成分，使其易于从肠道吸收。胰岛素是由内分泌胰腺的特殊细胞（称为β细胞）产生的。胰岛素控制血液中的血糖水平，并确保身体细胞获得足够的能量并可以储存能量以供以后使用。胰腺能够“感知”血液中的血糖水平——如果血糖水平过高，β细胞就会产生并分泌更多的胰岛素。如果水平太低，它的分泌就会减少。在某些情况下，不仅需要更多的胰岛素，而且β细胞的数量也需要增加，才能应对胰岛素需求的增加。这些情况包括正常衰老、怀孕和肥胖等。在上述情况下，如果不能增加β细胞的数量，可能会导致血糖水平升高和糖尿病。我们对胰腺如何在需要时增加β细胞的数量知之甚少。因此，确定控制这一适应性过程的因素非常重要。这项研究的目的是准确确定一个基因（我们认为是胰腺生长和功能的主要调节因子）实际上是如何发挥作用的。该基因编码一种与胰岛素相似的蛋白质 - 建议将其称为胰岛素样生长因子 2 (Igf2)。我们有初步证据表明，Igf2 是控制胰腺正常发育并在需要时使 β 细胞增殖的重要因素。我们许多试图破译对人类健康和疾病重要的机制的尝试都依赖于并受益于动物模型的研究。在这项研究中，我们将使用小鼠，因为它们的胰腺与人类相似，而且我们可以去除它们的 β 细胞或整个胰腺中的 Igf2 基因，从而使我们能够了解该基因的工作原理。我们还可以增加 β 细胞或整个胰腺产生的 Igf2 数量。我们将研究不能产生 Igf2 或比正常小鼠产生更多 Igf2 的胰腺的发育和结构。我们将特别关注 Igf2 缺乏或过多对胰腺发育和衰老过程中 β 细胞数量的影响。我们还将研究在正常怀孕期间、小鼠接受高脂肪饮食（模仿人类肥胖）期间或胰腺受伤时，Igf2 数量的变化如何影响胰腺产生新 β 细胞的方式。我们将利用这些实验来找出哪些其他基因受到 Igf2 的控制。这项研究的结果将有助于更好地了解胰腺如何发育、它在正常情况下如何工作以及它如何适应增加胰岛素需求的条件。

项目成果

Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes.

• DOI: 10.1002/emmm.201101105
• 发表时间: 2012-08
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Haley, Victoria L.;Barnes, David J.;Sandovici, Ionel;Constancia, Miguel;Graham, Christopher F.;Pezzella, Francesco;Buehnemann, Claudia;Carter, Emma J.;Hassan, A. Bassim
• 通讯作者: Hassan, A. Bassim

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

Mesenchymal Igf2 is a major paracrine regulator of pancreatic growth and function

间充质 Igf2 是胰腺生长和功能的主要旁分泌调节剂

• DOI: 10.1101/714121
• 发表时间: 2019
• 作者: Hammerle C

Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis.

• DOI: 10.1038/ncomms9265
• 发表时间: 2015-09-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ferrón SR;Radford EJ;Domingo-Muelas A;Kleine I;Ramme A;Gray D;Sandovici I;Constancia M;Ward A;Menheniott TR;Ferguson-Smith AC
• 通讯作者: Ferguson-Smith AC

Fetal manipulation of maternal metabolism is a critical function of Igf2 imprinting

胎儿对母体代谢的操纵是 Igf2 印记的关键功能

• DOI: 10.1101/2023.04.19.537510
• 发表时间: 2023
• 作者: Lopez-Tello J