Dietary Regulation of Pancreatic Digestive Enzymes

胰腺消化酶的饮食调节

基本信息

批准号：
6772422
负责人：
JOHN A WILLIAMS
金额：
$ 35.03万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-21 至 2007-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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 elF2 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 calcincunn-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 cyclosponn 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.

描述（由申请人提供）：每顿饭后不久，胰腺就会分泌消化各种膳食成分所需的大部分酶。为了使可用消化酶的量与消化需要相匹配，消化酶的合成和腺体的大小都受到调节。这部分是通过刺激消化酶分泌的激素和神经递质，特别是胆囊收缩素（CCK），但也通过饮食成分，特别是氨基酸。拟议工作的目的是描述这种调节的特征，揭示分子机制，并将刺激机制与综合反应联系起来。该提案的具体目标包括：（1）确定食物、氨基酸和CCK诱导胰腺消化酶合成的作用和机制。我们将首先确定喂养后小鼠胰腺蛋白质合成增强的时间过程和程度。将评估翻译起始因子（特别是 eIF2 和 eIF4E）以及 p70 核糖体 S6 激酶的激活状态。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翻译机制的信号的作用。我们还将确定 CCK、氨基酸和胰岛素在调节蛋白质合成中的相对重要性和协同作用。 (2)我们将确定CCK和氨基酸促进胰腺生长的作用。我们将确定在缺乏 CCK 的情况下膳食蛋白质对 MAP 激酶和其他生长介导途径的影响，并且我们将确定在缺乏 CCK 的情况下饮食诱导的生长是否依赖于钙调神经磷酸酶，类似于 CCK 在正常情况下的影响饮食。 (3)我们将确定钙调神经磷酸酶诱导胰腺蛋白质合成和生长的机制。将确定活化的钙调神经磷酸酶是否足以诱导生长和蛋白质合成。我们还将确定钙化诱导的基因调控是否参与生长反应。这些研究将在喂食不同饮食或灌胃饲喂胰蛋白酶抑制剂或氨基酸的正常小鼠中进行。他们还将利用 CCK 缺失的突变小鼠系，并构建具有针对胰腺的组成型活性钙调神经磷酸酶的转基因小鼠系。研究将在体内和分离的胰腺腺泡中进行。免疫抑制剂如cyclosponn A和FK506将用于抑制钙调神经磷酸酶和雷帕霉素来抑制mTOR。除了了解正常功能之外，这项工作还可能有助于设计饮食，以最大程度地刺激胰腺生长，以抵消胰腺功能不全。