CCK-58 and the Two Component Paradigm for Exocrine Pancreatic Secretion

CCK-58 和外分泌胰腺分泌的两部分范式

• 批准号: 7362011
• 负责人: GARY M GREEN
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7362011
• 关键词: Accounting; Acetylcholine; Acinar Cell; Acinus organ component; Acute; Animal Model; Animals; Area; Atrophic; Attention; Bicarbonates; Blood; Bombesin; Cell secretion; Cells; Chloride Channels; Chloride Ion; Chlorides; Cholecystokinin; Chronic; Copper; Coupled; Coupling; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytoplasmic Granules; Diet; Disease; Duct (organ) structure; Ductal; Duodenum; Electrolytes; Enzymes; Exocrine pancreas; Exocytosis; Exploratory/Developmental Grant; Fluids and Secretions; Functional disorder; Hormonal; Hormones; Human; In Vitro; Investigation; Knowledge; Left; Liquid substance; Localized; Measures; Minor; Modeling; Modification; Molecular; Names; Organ; Output; Pancreas; Pancreatic Diseases; Pancreatic Exocrine Secretion; Pancreatic duct; Pancreatitis; Preparation; Protein Secretion; Proteins; Rattus; Regulation; Relative (related person); Research; Role; Secretin; Sincalide; Solutions; Source; Stimulus; Structure-Activity Relationship; Swelling; System; Testing; Thick; Trees; Uncertainty; Water; Zymogen Granules; apical membrane; aqueous; base; cell type; cholecystokinin 58; day; experience; in vivo; inhibitor/antagonist; neglect; pancreatic juice; receptor; relating to nervous system; response; secretory protein; uptake

DESCRIPTION (provided by applicant): The exocrine pancreas produces a large amount (1-2 L/day) of an aqueous secretion containing enzymes and electrolytes. A long-standing paradigm states that the aqueous portion is regulated separately from the enzyme-containing portion, and that the two secretions originate from separate cell types. This is called the two-component hypothesis. One component, the acinar cell, synthesizes and packages the enzymes in zymogen granules, which are discharged into the duct system via exocytosis (called regulated secretion), and the second component, the aqueous component, secreted by the duct cells, dilutes the enzymes with an alkaline solution and the mixture enters the duodenum. The first component, enzymes, is regulated predominately by cholecystokinin and acetylcholine at the acinar cell. The second component, the aqueous, by secretin stimulation of duct cells (in combination with other secretagogues). We propose a modification of this paradigm. In our hypothesis, the acinar cell contributes a substantial volume (equal to duct cells) to the aqueous secretion, and the relationship of the amount of water/electrolyte to the amount of enzyme is tightly regulated. This regulation takes the form of electrolytes (K+, Cl-, HCO3-) entering the zymogen granule and osmotically drawing in water, and causing the granules to swell, often more than doubling their volume. We suggest that this zymogen granule water is the primary secretion of the acinar cell during regulated secretion. At this point, the granule matrix, diluted with water, is discharged into the ductal system where further dilution with ductal secretions occurs. The volume of granule water discharged into the ductal tree by exocytosis can account for all the fluid initially secreted in response to a strong stimulus (neural or hormonal). These steps are well established in many cell types, including the exocrine pancreas. However, their relevance to pancreatic function and disorders have received little attention, in part, we believe, because it represents a major departure from the widely-accepted two-component paradigm, in that it implies that a major fraction of the aqueous component (acinar fluid) and enzyme component are NOT separately regulated, and do NOT originate from separate cell types. This hypothesis has not been tested, because fluid secretion from acinar cells has never been quantified, in contrast to duct fluid, which has been studied in vitro in isolated pancreatic ducts, and in vivo using a rat model in which the acinar cells are completely eliminated but duct cells remain intact and functional. We will use this model, the copper-deficient rat, to test the hypothesis that the hormone, cholecystokinin-58, stimulates a large amount water and protein from the acinar cell, but not from the duct cells, and that this CCK-58 stimulated fluid secretion (but not secretin-stimulated fluid) will be abolished in copper-deficient rats. CCK-58 is unique, because it is the only form in rat blood and the only form that strongly stimulates water and chloride from the pancreas. The results may be highly relevant to the pancreatic disorders pancreatitis and cystic fibrosis. Project narrative: The disorders of the exocrine pancreas, the most important organ for secreting the digestive enzymes, is subject to several disorders, such as cystic fibrosis and pancreatitis. Our study will test a new hypothesis on how the secretions are regulated that may suggest new treatments for these diseases

描述（由申请人提供）：胰腺外分泌产生大量（1-2 L/天）含有酶和电解质的水性分泌物。一个长期存在的范式指出，水的部分是从含酶的部分分开调节，这两种分泌物来自不同的细胞类型。这就是所谓的双成分假说。一种成分，腺泡细胞，合成并包装酶原颗粒中的酶，酶原颗粒通过胞吐作用（称为调节分泌）排入导管系统，第二种成分，导管细胞分泌的水性成分，用碱性溶液稀释酶，混合物进入十二指肠。第一种成分是酶，主要由腺泡细胞中的胆囊收缩素和乙酰胆碱调节。第二个组成部分，水，通过分泌素刺激导管细胞（与其他促分泌素结合）。我们提出了一个修改这个范例。在我们的假设中，腺泡细胞贡献了大量的水分泌物（等于导管细胞），并且水/电解质的量与酶的量的关系受到严格的调节。这种调节以电解质（K+，Cl-，HCO 3-）的形式进入酶原颗粒并吸收水分，导致颗粒膨胀，通常体积增加一倍以上。我们认为，这种酶原颗粒水是在调节分泌的腺泡细胞的主要分泌。此时，用水稀释的颗粒基质被排放到导管系统中，在导管系统中发生导管分泌物的进一步稀释。通过胞吐作用排入导管树的颗粒水的体积可以解释最初响应于强刺激（神经或激素）而分泌的所有流体。这些步骤在许多细胞类型中得到了很好的建立，包括外分泌胰腺。然而，它们与胰腺功能和疾病的相关性很少受到关注，我们认为，部分原因是它代表了广泛接受的双组分范式的重大偏离，因为它意味着水组分（腺泡液）和酶组分的主要部分不是单独调节的，并且不是来自不同的细胞类型。这一假设尚未得到验证，因为腺泡细胞的液体分泌从未被定量，与导管液相反，导管液已在体外分离的胰腺导管中进行了研究，并在体内使用大鼠模型进行了研究，在该模型中腺泡细胞被完全消除，但导管细胞保持完整和功能。我们将使用这个模型，铜缺乏大鼠，以测试的假设，激素，胆囊收缩素-58，刺激大量的水和蛋白质从腺泡细胞，但不是从导管细胞，和CCK-58刺激的液体分泌（但不是分泌素刺激的液体）将被取消在铜缺乏大鼠。CCK-58是独一无二的，因为它是大鼠血液中唯一的形式，也是唯一能强烈刺激胰腺中水和氯的形式。结果可能与胰腺疾病胰腺炎和囊性纤维化高度相关。 项目说明：胰腺是分泌消化酶的最重要器官，其外分泌系统的疾病易发生多种疾病，如囊性纤维化和胰腺炎。我们的研究将测试一个新的假设，即分泌物是如何调节的，这可能会为这些疾病提供新的治疗方法。