Regulation of pancreatitis severity

胰腺炎严重程度的调节

• 批准号: 9140625
• 负责人: Fred Sanford Gorelick
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140625
• 关键词: Acinar Cell; Acinus organ component; Acute; Affect; Aftercare; Age; Alcohol abuse; Animal Model; Binding; Biological Markers; Ca(2+)-Transporting ATPase; Cardiac; Cause of Death; Cell membrane; Cell model; Cholelithiasis; Chronic Kidney Failure; Clinical; Data; Development; Disease; Figs - dietary; Gastrointestinal Diseases; Genetic; Goals; Heart; Hospitalization; Human; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Injury; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Lead; Measures; Mediating; Modeling; Mus; Onset of illness; Organ; PMCA1 protein; Pancreas; Pancreatitis; Pathologic; Patients; Peptides; Phenotype; Plasma; Population; Protein Isoforms; Recombinants; Regulation; Risk; Risk Factors; Role; Serum; Serum Proteins; Severities; Severity of illness; Signal Transduction; Small Interfering RNA; Therapeutic Agents; Time; Tissues; Veterans; Work; acute pancreatitis; aging population; cell injury; falls; improved; in vivo; inhibitor/antagonist; knock-down; mouse model; novel; novel therapeutics; protective effect; public health relevance; response; secretory protein; therapeutic target; tool

 DESCRIPTION (provided by applicant): This proposal will examine a newly described secretory protein, renalase, which appears to have a novel protective effect in acute pancreatitis (AP). AP has an incidence of up to 5/10,000, can cause death in 30% of those with severe disease, and is the most common reason for hospitalization for individuals with gastrointestinal disease. Since the disease is often caused by alcohol abuse and increases in incidence with age, it is frequently encountered in our Veteran population. Moreover, the risks for both developing AP and for severe disease are increased in chronic renal failure (CRF). Since CRF is common in our aging population of Veterans, it represents another relevant risk factor. We propose to study renalase, a serum protein that is produced in the kidneys and other tissues, that disappears from the serum with renal disease and other acute injuries. Renalase appears to have a potent protective pro-survival effect in the kidneys. We hypothesize that renalase will also have a protective role in AP and that decreases in renalase (serum and tissue) during some forms of injury, including acute pancreatitis, will result in more severe disease. We will examine the hypothesis with the following Specific Aims: 1) Determine whether serum renalase levels correlate with the presence of pancreatitis and its severity by examining its levels in sera and tissues from murine models of AP and in sera from patients with acute pancreatitis and controls; 2) Examine the effects of genetic deletion, peptide inhibition, and CRF on the severity of experimental murine AP; 3) Investigate whether exogenous recombinant renalase reduces severity of experimental acute pancreatitis in murine models and in human pancreatic acinar cells; 4) Determine whether the protective effects of renalase on pancreatitis-associated acinar cell injury is mediated by renalase activation of the plasma-membrane Ca2+ ATPase (PMCA) and Ca2+- extrusion. Mild and severe models of murine AP will be examined. Our preliminary data show the following: i) Serum renalase levels significantly decrease more than 50% within 2 hrs. after the initiation of murine AP and in humans with AP; ii) Genetic deletion of renalase results in a more severe phenotype of murine AP than wild- type controls; iii) Administering recombinant renalase reduces pancreatitis injury in isolated acinar cells and decreases the severity of murine AP in vivo whether given before or after disease onset; iv) Renalase binds to an isoform of the PMCA (PMCA4b) and enhances Ca2+-efflux from the pancreatic acinar cell; iv) PMCA inhibition enhances injury of acinar cells in pancreatitis. Our preliminary data firmly supports our hypothesis and demonstrates that we have the unique tools needed to complete the planned studies. The proposed work has the potential to provide a biomarker for pancreatitis and, more importantly, to characterize an attractive therapeutic target.

 描述（由申请人提供）： 该提案将检查一种新描述的分泌蛋白肾酶，它似乎对急性胰腺炎 (AP) 具有新的保护作用，AP 的发病率高达 5/10,000，可导致 30% 的重症患者死亡。这是胃肠道疾病患者住院的最常见原因，因为该疾病通常是由胃肠道疾病引起的。 酗酒以及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，此外，由于慢性肾衰竭 (CRF) 在我们的老龄化退伍军人群体中很常见，因此患 AP 和严重疾病的风险也会增加。 ，它代表了另一个相关的危险因素。肾酶是一种在肾脏和其他组织中产生的血清蛋白，它在肾脏疾病和其他急性损伤时从血清中消失，肾酶似乎具有有效的保护性促生存作用。对肾脏的作用。肾酶在 AP 中也具有保护作用，并且在某些形式的损伤（包括急性胰腺炎）期间肾酶（血清和组织）的减少将导致更严重的疾病，我们将通过以下具体目标来检验该假设：1）通过检查 AP 小鼠模型的血清和组织以及急性胰腺炎患者和对照血清中的肾酶水平，确定血清肾酶水平是否与胰腺炎的存在及其严重程度相关 2) 检查；基因缺失、肽抑制和 CRF 对实验性小鼠 AP 严重程度的影响；3) 研究外源性重组肾酶是否对小鼠模型和人胰腺腺泡细胞中实验性急性胰腺炎的严重程度有影响；4) 确定肾酶是否对实验性急性胰腺炎的严重程度有保护作用；胰腺炎相关腺泡细胞损伤是由质膜 Ca2+ ATP 酶 (PMCA) 和 Ca2+- 肾酶激活介导的我们将检查小鼠 AP 的轻度和重度模型： i) 小鼠 AP 发生后 2 小时内血清肾酶水平显着降低 50% 以上； ii) 遗传；删除肾酶会导致小鼠 AP 的表型比野生型对照更严重；体内，无论是在疾病发作之前还是之后给予；iv) 肾酶与 PMCA (PMCA4b) 的同种型结合并增强胰腺腺泡细胞的 Ca2+ 流出；iv) PMCA 抑制增强胰腺腺泡细胞的损伤； 我们的初步数据有力地支持了我们的假设，并证明我们拥有完成计划研究所需的独特工具，有可能为胰腺炎提供生物标志物，更重要的是，可以描述一个有吸引力的治疗靶点。