Role of the imprinted Igf2 gene in pancreatic development and function

胰腺是人体中的一个大腺体，具有两个非常重要的功能：它制造胰岛素和消化酶。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的成分，使其易于从肠道吸收。胰岛素是由内分泌胰腺中称为β细胞的特殊细胞产生的。胰岛素控制血糖水平，确保身体细胞获得足够的能量，并将其储存起来供日后使用。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，它分泌较少。有条件时，不仅需要更多的胰岛素，但β细胞的数量需要增加，以科普对胰岛素的需求增加。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，确定控制这种自适应过程的因素是非常重要的。这项研究的目的是精确地确定一个基因是如何工作的，我们认为它是胰腺生长和功能的主要调节因子。该基因编码一种类似于胰岛素的蛋白质-它被称为胰岛素样生长因子2（Igf 2）。我们有初步证据表明，Igf 2是控制胰腺正常发育的重要因素，并在需要时使β细胞增殖。我们许多试图破译对人类健康和疾病至关重要的机制的尝试都依赖于动物模型的研究，并从中受益。在这项研究中，我们将使用小鼠，因为它们的胰腺与人类的胰腺相似，因为我们可以去除它们的β细胞或整个胰腺中的Igf 2基因，使我们能够了解这个基因是如何工作的。我们还可以增加β细胞或整个胰腺中产生的Igf 2的量。我们将研究不能产生Igf 2或产生比正常小鼠多的Igf 2的胰腺的发育和结构。我们将特别关注Igf 2缺乏或过量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妊娠期间，在小鼠暴露于高脂肪饮食（模拟人类肥胖）或胰腺受伤时，改变Igf 2的量如何影响胰腺制造新β细胞的方式。我们将使用这些实验来发现哪些其他基因受Igf 2的控制。这项研究的结果将有助于更好地了解胰腺是如何发育的，它在正常情况下是如何工作的，以及它如何适应增加胰岛素需求的条件。

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.