Dietary Regulation of Pancreatic Digestive Enzymes

胰腺消化酶的饮食调节

基本信息

批准号：
6544038
负责人：
JOHN A WILLIAMS
金额：
$ 36.7万
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 2007-06-30
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，胰腺分泌了消化多种饮食成分所需的大多数酶。为了使可用的消化酶的数量与消化需求相匹配，调节了消化酶的合成和腺体的大小。这部分是通过激素和神经递质刺激消化酶分泌的激素和神经递质的，尤其是胆囊动蛋白（CCK），也是饮食成分，尤其是氨基酸。提出的工作是表征这种调节，揭示分子机制并将刺激机制与综合反应联系起来的目的。该提案的具体目的包括：（1）确定食物，氨基酸和CCK诱导胰腺消化酶的作用和机制。我们将首先建立进食后小鼠胰腺蛋白合成增强的时间过程和程度。将评估翻译起始因子的激活状态，尤其是ELF2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的作用，作为引发蛋白质合成并激活翻译机制的信号。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和氨基酸增强胰腺生长的作用。我们将在不存在CCK的情况下确定饮食蛋白对MAP激酶和其他介导途径的影响，我们将确定在没有CCK的情况下饮食诱导的生长是否取决于钙调蛋白，类似于CCK对正常饮食的影响。（3）我们将确定钙调神经蛋白酶在胰蛋白合成和生长诱导中的机制。活化的钙调蛋白是否足以诱导生长，并确定蛋白质合成。我们还将确定Calcincunn诱导的基因调节是否参与生长反应。这些研究将在喂养不同饮食或饲喂胰蛋白酶抑制剂或氨基酸的正常小鼠中进行。他们还将利用带有CCK删除的突变小鼠线，并涉及构造具有胰腺的组成型活性钙调蛋白的转基因小鼠系。研究将在体内和孤立的胰腺acini中进行。诸如Cyclosponn A和FK506之类的免疫抑制剂将用于抑制钙调蛋白和雷帕霉素抑制MTOR。这项工作除了了解正常功能外，还可以帮助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。