Acute Pancreatitis: Renalase as a novel target and agonists as new therapy

项目摘要/摘要 这一提议汇集了一支拥有多样化和互补性专业知识的顶尖团队，以开发一种新颖的 基于新发现的血清蛋白肾酶(RNLS)的治疗剂治疗急性胰腺炎 (美联社)。这种蛋白在急性组织损伤模型中似乎有一种新的保护作用，包括AP。 在美国，AP每年影响超过25万人，并可导致30%的重症患者死亡 疾病。这是美国胃肠道疾病患者住院治疗的最常见原因。 疾病。RNLS在肾脏和包括胰腺在内的其他组织中产生。 初步数据显示：1)小鼠急性胰腺炎发作后，血清RNLS迅速下降 2)RNLS基因缺失增加了实验性急性小鼠的严重程度 重组RNLS(RRNLS)降低小鼠胰腺炎反应 4)外源性rRNLS可显著降低小鼠急性胰腺炎的严重程度 体内的胰腺炎，无论是作为治疗前给药，还是在发病后两小时给药。首字母 研究表明，RNLS衍生的多肽可以减轻几种类型培养细胞的急性损伤。这 保护作用局限于RNLS的C-末端区域。这些发现表明，RNLS 将对美联社起到保护作用。 拟议的研究将检查RNLS衍生的多肽，并将它们的效力与rRNLS进行比较 在减少AP损伤方面的作用。由于易于制造，这些多肽可能比rRNLS具有优势 和更强大的专利地位。将选择和审查含铅药物，具体目标如下： 1)RNLS和RNLS派生的较小的多肽将进行比较/优先排序，以确定其降低 分离的小鼠胰腺腺泡细胞的胰腺炎反应。2)rRNLS对AP严重程度的影响 在目标1中确定的两种最有效的多肽将在两只实验小鼠身上进行测试 模型：大剂量雨蛙素诱导的轻度AP和大剂量雨蛙素诱导的严重AP模型 腹膜内酒精和一种脂肪酸。为了进一步反映临床治疗方案， RRNLS或相关多肽在受伤前或发病后给予时将进行检查。 疾病。此外，AP的传统生化指标将与RNLS水平以及 疼痛，急性胰腺炎的关键症状。随着项目的成功，该项目将进入后期阶段 一种新颖、设计合理的治疗药物的开发和临床研究。基于中国的实力 初步数据和证据表明，这种新的生存途径在两种疾病中都是根本重要的 在小鼠模型和人类疾病中，RNLS疗法具有非常高的潜力 预防或治疗急性胰腺炎。

Project Summary/Abstract This proposal brings together a top team with diverse and complementary expertise to develop a novel therapeutic agent based on a newly described serum protein, renalase (RNLS) to treat acute pancreatitis (AP). This protein appears to have a novel protective effect in models of acute tissue injury, including AP. AP affects more than 250,000 people/year in the USA and can cause death in 30% of those with severe disease. It is the most common reason for hospitalization in the USA for individuals with gastrointestinal disease. RNLS is produced in the kidneys and other tissues including the pancreas. Initial data show that: 1) Serum RNLS rapidly decreases soon after the onset of AP in a murine model and in humans; 2) Genetic deletion of RNLS increases the severity of experimental acute murine pancreatitis; 3) Recombinant RNLS (rRNLS) reduces pancreatitis responses in isolated murine pancreatic acinar cells; 4) Exogenous rRNLS significantly reduces the severity of acute murine pancreatitis in vivo when given either as pretreatment or two hours after the onset of disease. Initial studies show that RNLS-derived peptides reduce acute injury in several types of cultured cells. This protective effect has been localized to the C-terminal region of RNLS. These findings suggest that RNLS will have a protective role in AP. The proposed studies will examine RNLS-derived peptides and compare their potency to rRNLS in reducing AP injury. The peptides may have advantages over rRNLS by way of ease of manufacture and stronger patent position. Lead drugs will be selected and examined with the following Specific Aims: 1) RNLS and RNLS-derived, smaller peptides will be compared/prioritized for their potency in reducing pancreatitis responses in isolated murine pancreatic acinar cells. 2) The effects on AP severity of rRNLS and the two most potent peptides identified in Aim 1 will be examined in two experimental murine models: a mild form of AP induced by high doses of cerulein and a severe model of AP induced by intraperitoneal alcohol and a fatty acid. To further reflect clinical treatment scenarios, the effectiveness of rRNLS or related peptides will be examined when given prior to the onset of injury or after the onset of disease. Further, traditional biochemical measures of AP will be correlated with RNLS levels as well as pain, a key symptom of acute pancreatitis. With success the project will be poised for late stage development and clinical studies of a novel and rationally designed therapeutic. Based on the strength of the preliminary data and evidence that this novel survival pathway is fundamentally important in both murine models and human disease, RNLS therapy has a very high potential for being effective in preventing or treating AP.