Acinar Biology and Pancreatic Disease

腺泡生物学和胰腺疾病

基本信息

批准号：
9457119
负责人：
GUY E GROBLEWSKI
金额：
$ 33.38万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/9457119
关键词：
Acinar Cell Admission activity Adult American Animals Apical Attention Automobile Driving Autophagocytosis Binding Biology Cell model Cell physiology Critical Pathways Crohn&apos s disease Data Development Disease Down-Regulation Elastases Enzyme Precursors Enzymes Event Exocrine pancreas Gland Goblet Cells Grant Homeostasis Hospitals Human Impairment Inflammatory Response Intestines 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 insight late endosome mortality prevent response therapeutic target trafficking trait transcription factor tumor vesicle-associated membrane protein

项目摘要

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.

胰腺炎是与胃肠道相关的医院入院的最常见原因，经济影响每年总计37亿美元，但除姑息治疗以外的治疗方案很少。急性的启动胰腺炎在很大程度上是由于在主要细胞类型中激活蛋白水解酶原引起的腺体，腺泡细胞。腺泡细胞的损伤导致细胞因子/趋化因子引起的炎症反应可能会传播到其他器官系统，可能是致命的。腺泡细胞从A中进行消化酶分泌主要途径称为酶原颗粒途径，并且不太公认的本构样途径（CLP）。 CLP利用顺行内体贩运来分泌少量的消化酶，因此，仅受到有限的关注。我们已发布和初步数据发现了以前在1）塑料ZG介导的分泌的CLP的函数，2）控制细胞内 Zymogen激活，3）维持转录因子SXBP1的表达，这对于腺泡至关重要分化和4）根据分泌活动来协调自噬水平。所有这些过程与AP的开发和发展有关，但腺泡细胞如何整合这些途径以及它们相互依存的程度尚不清楚。肿瘤蛋白D52玩A 关键作用在调节CLP中。我们已经确定D52是一种自噬蛋白，与自噬的主要调节剂ATG16L1是突变时是与克罗恩病的发展。该提案研究了总体假设，即D52调节 CLP在协调分泌功能和高水平的自噬中起着核心作用保持腺泡细胞稳态。 AIM 1利用D52敲除小鼠来测试D52调节的假设顺行内体贩运对于维持腺泡末端分化至关重要，而D52-的丧失介导的贩运将对胰腺炎的恢复产生负面影响。 AIM 2将评估机械角色 D52-ATG16L1在控制腺泡稳态时的相互作用正常和胰腺炎期间。目的 3将检验以下假设，即小鼠ATG16L1的嗜血突变将对胰腺产生负面影响腺泡细胞功能使动物更容易受到体内AP的发展。这些研究应该为确定旨在治疗胰腺炎的治疗靶标和策略提供了重要的见解。