Dietary Regulation of Pancreatic Digestive Enzymes

胰腺消化酶的饮食调节

• 批准号: 7584963
• 负责人: JOHN A WILLIAMS
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-21 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584963
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Acinus organ component; Amino Acids; Biochemical; Branched-Chain Amino Acids; Calcineurin; Calcium; Cholecystokinin; Cyclosporine; Diet; Dietary Component; Dietary Proteins; Digestion; Enzymes; Exocrine pancreatic insufficiency; FK506; Facility Construction Funding Category; Food; Gene Expression Regulation; Gland; Growth; Hormones; Immunosuppressive Agents; In Vitro; Individual; Insulin; Intestinal Hormones; Leucine; Measurement; Mediating; Mitogen-Activated Protein Kinases; Molecular; Mus; Mutant Strains Mice; Neurotransmitters; Nutrient; Pancreas; Pathway interactions; Peptide Initiation Factors; Play; Protein Biosynthesis; Proteins; Purpose; Regulation; Relative (related person); Ribosomal Protein S6 Kinase; Role; ST5 Protein; ST5 gene; Signal Transduction; Sirolimus; Time; Transcriptional Regulation; Transgenic Mice; Translational Regulation; Translations; Trypsin Inhibitors; Work; activating transcription factor; base; calcineurin phosphatase; design; feeding; human FRAP1 protein; in vivo; response; size

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.

每餐后不久，胰腺就会分泌消化多种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量与消化需要相匹配，两者 消化酶的合成和腺体的大小受到调节。这部分是通过激素和 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联系起来 回复。该提案的具体目标包括： 1) 确定食物、氨基酸的作用和机制 酸和CCK诱导胰腺消化酶的合成。我们将首先确定时间进程并 喂养后小鼠胰腺蛋白质合成增强的程度。翻译激活状态 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 翻译机械。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。我们将确定在缺乏 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，我们将确定在没有 CCK 的情况下饮食诱导的生长是否有效 依赖于钙调神经磷酸酶，类似于正常饮食中 CCK 的作用。 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。是否是活化的钙调神经磷酸酶 将确定足以诱导生长和蛋白质合成的量。我们还将确定是否 钙调神经磷酸酶诱导的基因调控参与生长反应。这些研究将在 正常小鼠饲喂不同的饮食或灌胃饲喂胰蛋白酶抑制剂或氨基酸。他们还将利用 缺失CCK的突变小鼠系，并涉及构建具有组成型的转基因小鼠系 针对胰腺的活性钙调神经磷酸酶。研究将在体内和离体胰腺中进行 腺泡。环孢素A和FK506等免疫抑制剂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之外，还可能有助于设计饮食以 最大限度地刺激胰腺生长，以抵消胰腺功能不全。