Regulation of pancreatitis severity

胰腺炎严重程度的调节

基本信息

批准号：
10013408
负责人：
Fred Sanford Gorelick
金额：
--
依托单位：
VA CONNECTICUT HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013408
关键词：
Acinar Cell Acute Affect Age Alcohol abuse Animal Model Antibodies Appearance Award Binding Proteins Biological Process Biology Blood Blood Proteins Calcium Cause of Death Cell membrane Cell model Cessation of life Cholelithiasis Clinical Complication Data Disease Drug or chemical Tissue Distribution Exocrine pancreatic insufficiency Failure Foundations Funding Future Gastrointestinal Diseases Gene Expression Genetic Hospitalization Human Immunoprecipitation Incidence Individual Inflammatory Injury Kidney Lead Manuscripts Mass Spectrum Analysis Mediating Mediator of activation protein Messenger RNA Modeling Monitor Multiple Organ Failure Mus Onset of illness Pancreas Pancreatic Diseases Pancreatitis Patients Pattern Phase Plasma Plasma Proteins Population Prognostic Factor Protein Family Proteolysis Publishing Pump Recombinants Recovery Regulation Reporting Resolution Risk Role Serum Severities Severity of illness Source Testing Therapeutic Therapeutic Agents Time Tissues Veterans Work acute pancreatitis alpha 2-Glucoproteins cigarette smoking clinically relevant disease natural history falls improved in vivo insight mRNA Expression military veteran mortality risk mouse model novel novel therapeutics protective effect protein purification protein transport reconstitution response secretory protein trafficking uptake

项目摘要

This proposal will continue the topic of our current Merit Award and examine a relatively recently described secretory protein, renalase, which appears to have a potent and novel protective role in acute pancreatitis (AP). AP has an incidence of up to 5/10,000 in the U.S. population, but is much more common in Veterans. It can cause death in 30% of those with severe disease, and is the most common reason for hospitalization for individuals with gastrointestinal disease in the U.S. Since AP is often caused by alcohol abuse, cigarette smoking, and increases in incidence with age, it is frequently encountered in our Veteran population. During this funding period we published a manuscript that examined most of our current Merit Aims on renalase in experimental murine AP and showed that: 1) Plasma renalase levels fell dramatically at the onset of AP and rebounded much higher than basal levels during recovery, 2) Genetic deletion of renalase was associated with worse experimental AP, 3) Administering recombinant renalase (rRNLS) reduced experimental AP severity in vivo even when given after disease onset, 4) rRNLS could act directly on pancreatic acinar cells to reduce injury, 5) The protective effects of renalase on acinar cells is mediated by a specific plasma-membrane calcium export pump (PMCA4b). Our preliminary studies in clinical AP suggest that plasma renalase levels also falls in human AP and may reflect disease severity. Here we propose to extend these observations with 3 specific aims that will examine the following questions: 1) Does renalase also affect recovery from acute pancreatitis? 2) What mechanisms account for the rapid decrease in plasma renalase and appearance in the kidney in experimental AP and the subsequent increases in plasma renalase during recovery? 3) Do plasma binding proteins interact with RNLS and how might it affect its biology? These issues are relevant when considering renalase as a potential AP therapy because the data could serve as a guide for its future administration by showing benefits when given well after disease onset to promote recovery. The plasma levels of renalase may be a prognostic factor for AP severity and could also guide therapies including administering renalase. The following preliminary data provides a scientific foundation for pursuing these questions and aims. First, we find that severe human AP is associated with levels of plasma renalase that are persistently lower than baseline, indicating a deficient. We propose to examine the levels of plasma renalase in other murine AP models, including one that causes severe disease, to determine whether they conform to the patterns in human. In mice with genetic deletion of renalase, we find that AP recovery is delayed. The human and AP model findings led us to predict that renalase may be act to both reduce the acute AP severity and enhance recovery- we will test this experimentally. Second, we observe that during AP, the levels of renalase in the kidney dramatically increase in the mouse kidney while the plasma levels reach their nadir; kidney renalase mRNA levels fall during this time, suggesting the absence of new kidney renalase synthesis. We conclude the acute kidney increase is likely due to sequestration. We also find that plasma renalase levels rebound well above baseline during experimental AP recovery. We propose to explore these responses by examining plasma renalase trafficking and turnover. The potential uptake and secretion by the kidney during AP onset and the source(s) of plasma renalase during AP recovery will also be examined. Third, we find that a major fraction of plasma renalase is bound to alpha-2-macroglobulin family proteins in murine plasma and predict that humans will be similar. We propose to explore the trafficking of these proteins during AP and their interactions with renalase. We believe that these studies in murine models should provide useful insights for future studies of renalase in clinical pancreatitis including its most appropriate potential uses as a as a therapeutic agent.

该提案将继续我们当前优异奖的主题，并研究最近描述的分泌蛋白肾酶似乎对急性胰腺炎（AP）具有有效且新颖的保护作用。 AP 在美国人口中的发病率高达 5/10,000，但在退伍军人中更为常见。它可以导致 30% 的重症患者死亡，是住院治疗的最常见原因在美国患有胃肠道疾病的人，因为 AP 通常是由酗酒、吸烟引起的吸烟，并且发病率随着年龄的增长而增加，在我们的退伍军人群体中经常遇到。在此期间资助期间，我们发表了一份手稿，检查了我们目前关于肾酶的大部分优点目标小鼠实验性 AP 并表明：1）血浆肾酶水平在 AP 发作时急剧下降，并且在恢复期间反弹远高于基础水平，2) 肾酶基因缺失与更严重的实验性 AP，3) 施用重组肾酶 (rRNLS) 可降低实验性 AP 严重程度即使在疾病发作后给予体内，4) rRNLS 可以直接作用于胰腺腺泡细胞以减少损伤， 5) 肾酶对腺泡细胞的保护作用是由特定的质膜钙输出介导的泵 (PMCA4b)。我们在临床 AP 中的初步研究表明，人类血浆肾酶水平也有所下降 AP 可以反映疾病的严重程度。在此，我们建议通过 3 个具体目标来扩展这些观察结果，检查以下问题： 1) 肾酶是否也影响急性胰腺炎的恢复？ 2) 什么实验中血浆肾酶快速下降和肾脏出现的机制 AP 以及随后恢复期间血浆肾酶的升高？ 3) 血浆结合蛋白相互作用吗 RNLS 及其如何影响其生物学？当考虑肾酶作为一种药物时，这些问题是相关的。潜在的 AP 疗法，因为数据可以通过显示其益处来作为未来管理的指南在疾病发作后不久给予以促进康复。血浆肾酶水平可能是一个预后指标影响 AP 严重程度的因素，还可以指导包括肾酶治疗在内的治疗。以下初步数据为追求这些问题和目标提供了科学基础。首先，我们发现严重的人类AP 与持续低于基线的血浆肾酶水平相关，表明存在缺陷。我们提议检查其他小鼠 AP 模型中的血浆肾酶水平，包括导致严重 AP 模型的血浆肾酶水平疾病，以确定它们是否符合人类的模式。在肾酶基因缺失的小鼠中，我们发现AP恢复有延迟。人类和 AP 模型的发现使我们预测肾酶可能起作用为了降低急性 AP 的严重程度并促进恢复——我们将对此进行实验测试。第二，我们观察到在 AP 期间，小鼠肾脏中肾酶的水平急剧增加，而血浆水平达到最低点；肾脏肾酶 mRNA 水平在此期间下降，表明不存在新肾肾酶合成。我们得出的结论是，肾脏急性增加可能是由于隔离所致。我们也发现在实验性 AP 恢复期间血浆肾酶水平反弹远高于基线。我们建议通过检查血浆肾酶运输和周转来探索这些反应。潜在的吸收和 AP 发作期间肾脏的分泌以及 AP 恢复期间血浆肾酶的来源也将被检查了。第三，我们发现血浆肾酶的主要部分与α-2-巨球蛋白家族结合小鼠血浆中的蛋白质和预测人类将是相似的。我们建议探讨这些物质的贩运问题 AP 期间的蛋白质及其与肾酶的相互作用。我们相信这些小鼠模型研究应该为肾酶在临床胰腺炎中的未来研究提供有用的见解，包括其最合适的潜力用作治疗剂。