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

项目总结/摘要 这项提案汇集了一个拥有多样化和互补专业知识的顶级团队， 基于新描述的血清蛋白肾酶（RNLS）的治疗急性胰腺炎的治疗剂 （美联社）这种蛋白质似乎在急性组织损伤（包括AP）模型中具有新的保护作用。 在美国，AP每年影响超过25万人，并可导致30%的重度AP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。 初步数据表明：1）在小鼠AP发病后不久，血清RNLS迅速下降， 2）RNLS的遗传缺失增加了实验性急性鼠白血病的严重程度， 胰腺炎; 3）重组RNLS（rRNLS）减少分离的鼠中的胰腺炎应答 胰腺腺泡细胞; 4）外源性rRNLS显著降低急性鼠胰腺炎的严重程度， 在治疗前或疾病发作后2小时给予时，体内胰腺炎。初始 研究表明RNLS衍生肽减少了几种类型培养细胞的急性损伤。这 保护作用已定位于RNLS的C-末端区域。这些发现表明，RNLS 对AP有保护作用。 拟议的研究将检查RNLS衍生的肽，并将其效力与rRNLS进行比较 减少AP损伤。所述肽可以通过易于制造而具有优于rRNLS的优点 更强的专利地位。将根据以下具体目的选择和检查先导药物： 1)RNLS和RNLS衍生的较小肽将比较/优先考虑它们在降低细胞毒性方面的效力。 分离的鼠胰腺腺泡细胞中的胰腺炎应答。2)rRNLS对AP严重程度的影响 在Aim 1中鉴定的两种最有效的肽将在两种实验鼠中进行检查 模型：高剂量雨蛙肽诱导的轻度AP模型和高剂量雨蛙肽诱导的重度AP模型。 腹膜内酒精和脂肪酸。为了进一步反映临床治疗方案， 当在损伤发作之前或损伤发作之后给予时，将检查rRNLS或相关肽。 疾病此外，AP的传统生物化学测量将与RNLS水平以及 疼痛是急性胰腺炎的主要症状。如果成功，该项目将进入后期阶段 开发和临床研究的一种新的和合理设计的治疗。基于 初步的数据和证据表明，这种新的生存途径是根本上重要的， 在小鼠模型和人类疾病中，RNLS疗法具有非常高的有效潜力， 预防或治疗AP。

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.