Dietary Regulation of Pancreatic Digestive Enzymes

每顿饭后不久，胰腺就会分泌消化各种不同食物所需的大部分酶。 一系列饮食成分。为了使可用消化酶的数量与消化需要相匹配， 消化酶的合成和腺体的大小是受调节的。这在一定程度上是通过激素和 刺激消化酶分泌的神经递质，特别是CCK，还通过 饮食成分，特别是氨基酸。拟议的工作的目的是描述这一点 调节，揭示分子机制，并将刺激机制与整合 回应。这项建议的具体目标包括：1)确定食物、氨基酸 酸和CCK诱导胰腺消化酶的合成。我们将首先确定时间进程和 喂食后小鼠胰腺蛋白质合成增强的程度。翻译的激活状态 启动因子，特别是eIF2和eIF4E，以及p70核糖体S6激酶将被评估。我们会 确定氨基酸，特别是亮氨酸的作用，作为启动蛋白质合成和激活 翻译机器。我们还将确定CCK、氨基酸和 胰岛素在调节蛋白质合成中的作用。2)我们将确定CCK和氨基酸增强 胰腺生长。我们将确定在没有CCK的情况下饮食蛋白质对MAP激酶和MAP的影响。 其他生长调节途径，我们将确定在没有CCK的情况下饮食诱导的生长是否 依赖钙调神经磷酸酶，与正常饮食中CCK的效果相似。3)我们将确定机制 钙调神经磷酸酶在诱导胰腺蛋白质合成和生长中的作用。激活的钙调神经磷酸酶是否 足以诱导生长和蛋白质合成的蛋白质将被确定。我们还将确定是否 钙调神经磷酸酶诱导的基因调控参与了生长反应。这些研究将在#年进行。 正常小鼠饲喂不同的日粮或灌胃胰蛋白酶抑制剂或氨基酸。他们还将利用一个 CCK缺失突变小鼠品系的构建及其转基因品系的构建 活性钙调神经磷酸酶以胰腺为靶点。研究将在体内和在离体胰腺中进行。 阿契尼。将使用环孢素A和FK506等免疫抑制剂来抑制钙调神经磷酸酶和雷帕霉素 抑制mTOR。这项工作，除了了解正常的功能外，可能有助于设计饮食 最大限度地刺激胰腺生长，以抵消胰腺功能不全。

The pancreas shortly after each meal secretes the majority of the enzymes required for digestion of a diverse array of dietary components. To match the amount of available digestive enzymes to digestive need, both the synthesis of digestive enzymes and the size of the gland are regulated. This is in part via the hormones and neurotransmitters that stimulate digestive enzyme secretion, particularly cholecystokinin (CCK), but also by dietary components, particularly amino acids. It is the purpose of the proposed work to characterize this regulation, uncover the molecular mechanisms, and relate the stimulatory mechanisms to the integrative response. Specific aims of this proposal include: 1) Determining the role and mechanism by which food, amino acids and CCK induce the synthesis of pancreatic digestive enzymes. We will first establish the time course and extent of enhanced pancreatic protein synthesis in mice after feeding. The state of activation of translation initiation factors, particularly eIF2 and eIF4E, and p70 ribosomal S6 kinase will be evaluated. We will determine the effects of amino acids particularly leucine as a signal to initiate protein synthesis and activate the translation machinery. We will also determine the relative importance and synergy of CCK, amino acids and insulin in regulating protein synthesis. 2) We will determine the role by which CCK and amino acids enhance pancreatic growth. We will determine the effects of dietary protein in the absence of CCK on MAP kinase and other growth mediating pathways, and we will determine if diet-induced growth in the absence of CCK is dependent on calcineurin, similar to the effect of CCK with a normal diet. 3) We will determine the mechanism of calcineurin in induction of pancreatic protein synthesis and growth. Whether activated calcineurin is sufficient to induce growth and protein synthesis will be determined. We will also determine whether calcineurin-induced gene regulation is involved in the growth response. These studies will be carried out in normal mice fed different diets or gavage-fed trypsin inhibitor or amino acids. They will also make use of a mutant mouse line with CCK deleted and involve the construction of a transgenic mouse line with constitutively active calcineurin targeted to the pancreas. Studies will be carried out both in vivo and in isolated pancreatic acini. Immunosuppressants such as cyclosporin A and FK506 will be used to inhibit calcineurin and rapamycin to inhibit mTOR. This work, in addition to understanding normal function may assist in designing diets to maximally stimulate pancreatic growth to counteract pancreatic insufficiency.