Dietary Regulation of Pancreatic Digestive Enzymes

每餐后不久，胰腺分泌消化各种食物所需的大部分酶。 一系列的饮食成分。为了使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受到调节。这部分是通过荷尔蒙和 刺激消化酶分泌的神经递质，特别是胆囊收缩素（CCK），但也通过 膳食成分，特别是氨基酸。拟议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 反应该提案的具体目标包括：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， 增强的胰腺蛋白质合成的程度在小鼠喂养后。翻译的激活状态 将评估起始因子，特别是eIF2和eIF4E，以及p70核糖体S6激酶。我们将 确定氨基酸，特别是亮氨酸作为启动蛋白质合成和激活细胞的信号的作用。 翻译机器我们还将确定CCK、氨基酸和 胰岛素调节蛋白质合成。2)我们将确定CCK和氨基酸增强的作用， 胰腺生长我们将确定在没有CCK的情况下，膳食蛋白质对MAP激酶的影响， 其他生长介导途径，我们将确定是否饮食诱导的生长在CCK的情况下， 依赖于钙调磷酸酶，类似于正常饮食的CCK的作用。3)我们将确定机制 钙调神经磷酸酶诱导胰腺蛋白合成和生长。激活的钙调神经磷酸酶是否 将确定足以诱导生长和蛋白质合成的量。我们还将确定 钙调神经磷酸酶诱导的基因调节参与生长反应。这些研究将在 正常小鼠喂食不同的饮食或管饲胰蛋白酶抑制剂或氨基酸。他们还将利用一个 CCK缺失的突变小鼠系，并涉及构建组成型CCK缺失的转基因小鼠系， 针对胰腺的活性钙调磷酸酶。研究将在体内和离体胰腺中进行。 腺泡。免疫抑制剂如环孢菌素A和FK506将用于抑制钙调神经磷酸酶和雷帕霉素 抑制mTOR。这项工作，除了了解正常功能可能有助于设计饮食， 最大限度地刺激胰腺生长以对抗胰腺功能不全。

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.