Acinar Biology and Pancreatic Disease

腺泡生物学和胰腺疾病

• 批准号: 9921376
• 负责人: GUY E GROBLEWSKI
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921376
• 关键词: Acinar Cell; Adult; American; Animals; Apical; Attention; Automobile Driving; Autophagocytosis; Binding; Biology; Cell model; Cell physiology; Critical Pathways; Crohn' s disease; Data; Development; Disease; Down-Regulation; Elastases; Enzyme Precursors; Enzymes; Event; Exocrine pancreas; Gland; Goblet Cells; Grant; Homeostasis; Hospitalization; Human; Impairment; Inflammatory Response; Knock-out; Knockout Mice; Link; Lysosomes; Maintenance; Malignant neoplasm of pancreas; Maps; Mediating; Morphology; Mucous body substance; Mus; Mutate; Mutation; Palliative Care; Pancreas; Pancreatic Diseases; Pancreatitis; Paneth Cells; Pathologic; Pathway interactions; Pharmacologic Substance; Physiological; Play; Point Mutation; Preparation; Process; Proteins; Publishing; RNA Splicing; Recovery; Regulation; Regulatory Pathway; Reporting; Rodent; Role; Secretory Vesicles; Series; Shapes; Site; Slice; System; TPD52 gene; Tamoxifen; Testing; Therapeutic; Trypsinogen; Zymogen Granules; acute pancreatitis; body system; cell type; cellular targeting; chemokine; cytokine; economic impact; experimental study; genetic regulatory protein; in vivo; inflammatory disease of the intestine; insight; late endosome; mortality; preservation; prevent; response; therapeutic target; trafficking; trait; transcription factor; tumor; vesicle-associated membrane protein

Pancreatitis is the most common reason for GI-disease related hospital admissions with an economic impact totaling $3.7 billion annually, yet few treatment options other than palliative care exist. The initiation of acute pancreatitis is largely held to result from activation of proteolytic zymogens within the major cell type of the gland, acinar cells. Damage of acinar cells results in a cytokine/chemokine-initiated inflammatory response that may spread to other organ systems and can be fatal. Acinar cells undergo digestive enzyme secretion from a major pathway termed the zymogen granule pathway, and less well recognized constitutive-like pathway (CLP). The CLP utilizes anterograde endosomal trafficking to secrete small quantities of digestive enzymes, and therefore has received only limited attention. Our published and preliminary data have uncovered a previously unrecognized function for the CLP in 1) shaping ZG-mediated secretion, 2) controlling intracellular zymogen activation, 3) maintaining expression of the transcription factor sXBP1 that is essential for acinar differentiation, and 4) coordinating levels of autophagy in accordance with secretory activity. All of these processes have been implicated in the development and progression of AP, yet how acinar cells integrate these pathways, and the extent to which they are interdependent remains unclear. Tumor protein D52 plays a pivotal role in regulating the CLP. We have determined that D52 is an autophagy protein that interacts with ATG16L1, a major regulator of autophagy, that when mutated is the most common marker associated with development of Crohn's disease. This proposal examines the overarching hypothesis that D52 regulation of the CLP plays a central role in coordinating secretory function and high levels of autophagy necessary to maintain acinar cell homeostasis. Aim 1 utilizes D52 knockout mice to test the hypothesis that D52-regulated anterograde endosomal trafficking is essential to maintain acinar terminal differentiation, and that loss of D52- mediated trafficking will negatively impact recovery from pancreatitis. Aim 2 will evaluate the mechanistic role of the D52-ATG16L1 interaction in controlling acinar homeostasis both normally and during pancreatitis. Aim 3 will test the hypothesis that hypomophic mutation of ATG16L1 in mice will negatively impact pancreatic acinar cell function making animals more susceptible to the development of AP in vivo. These studies should provide critical insights essential to identify therapeutic targets and strategies aimed at treating pancreatitis.

胰腺炎是胃肠道疾病相关住院的最常见原因，具有经济影响 每年总计37亿美元，但除了姑息治疗外，几乎没有其他治疗选择。急性期的起始 胰腺炎在很大程度上被认为是由胰腺的主要细胞类型内的蛋白水解酶原的激活引起的。 腺泡细胞。腺泡细胞的损伤导致细胞因子/趋化因子引发的炎症反应， 可能会扩散到其他器官系统，并可能致命。腺泡细胞经历消化酶分泌， 一个主要途径称为酶原颗粒途径，和较少被认识的组成型途径 （CLP）。CLP利用顺行内体运输分泌少量消化酶， 因此只受到有限的关注。我们公布的和初步的数据揭示了一个 以前未被认识到的CLP功能：1）塑造ZG介导的分泌，2）控制细胞内 酶原激活，3）维持转录因子sXBP 1的表达，sXBP 1是腺泡形成所必需的。 分化，和4）根据分泌活性协调自噬水平。所有这些 这些过程与AP的发展和进展有关，但腺泡细胞如何整合 这些途径以及它们相互依赖的程度仍不清楚。肿瘤蛋白D52发挥着重要作用。 在监管CLP方面发挥关键作用。我们已经确定D52是一种自噬蛋白， ATG 16 L1是自噬的主要调节因子，当突变时，它是与自噬相关的最常见标志物。 克罗恩病的发展。该提案检查了D52调节的总体假设， CLP在协调分泌功能和高水平的自噬方面起着核心作用， 维持腺泡细胞内环境稳定。目的1利用D52基因敲除小鼠来检验D52调节的细胞凋亡的假说。 顺行内体运输对于维持腺泡终末分化是必需的，并且D52- 介导的运输将对胰腺炎的恢复产生负面影响。目标2将评估机械作用 D52-ATG 16 L1相互作用在正常和胰腺炎期间控制腺泡内稳态。目的 3将检验小鼠中ATG 16 L1的低营养性突变将对胰腺炎产生负面影响的假设。 腺泡细胞的功能使动物在体内更容易发生AP。这些研究应 提供关键的见解至关重要，以确定治疗目标和战略，旨在治疗胰腺炎。