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

急性胰腺炎：肾酶作为新靶点和激动剂作为新疗法

基本信息

批准号：
9199635
负责人：
BARRY A BERKOWITZ
金额：
$ 30万
依托单位：
BESSOR PHARMA, LLC
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：
2016-09-20 至 2018-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199635
关键词：
Acinar Cell Acute Admission activity Affect Agonist Alcohols Amylases Binding Biochemical Biology C-terminal Ca(2+)-Transporting ATPase Calcium Cause of Death Cell Death Cell Survival Cell membrane Cell model Cells Cisplatin Clinical Clinical Research Clinical Treatment Creatinine Cultured Cells Data Development Disease Dose Edema Effectiveness Enzyme Precursors Ethanol Fatty Acids Gastrointestinal Diseases Generations Genetic Growth Healthcare Systems Hospitalization Hospitals Hour Human IL6 gene In Vitro Incidence Individual Infiltration Inflammation Inflammation Mediators Inflammatory Response Injury Innovative Therapy Kidney Lead Legal patent Link Lung Lung Inflammation Measures Mediating Metabolism Modeling Mus Onset of illness Pain Pancreas Pancreatitis Pathologic Pathway interactions Patients Peptides Peroxidases Pharmaceutical Preparations Positioning Attribute Protein Engineering Proteins Pulmonary Edema Recombinants Role Serum Serum Proteins Severities Severity of illness Signal Transduction Staging Symptoms Testing Therapeutic Therapeutic Agents Time Tissue Survival Tissues Trypsin Trypsinogen abstracting acute pancreatitis base body system design drug candidate drug development experience gastrointestinal human disease in vivo intraperitoneal macrophage mimetics mouse model neutrophil novel novel therapeutics palmitoleic acid peptide analog pre-clinical prevent protective effect response success

项目摘要

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.

项目概要/摘要该提案汇集了一支具有多元化和互补专业知识的顶级团队来开发一种新颖的基于新描述的血清蛋白肾酶（RNLS）的治疗剂可治疗急性胰腺炎（美联社）。这种蛋白质似乎对急性组织损伤模型（包括 AP）具有新颖的保护作用。在美国，AP 每年影响超过 250,000 人，并可导致 30% 的重症患者死亡疾病。这是美国胃肠道患者住院的最常见原因疾病。 RNLS 在肾脏和其他组织（包括胰腺）中产生。初步数据表明： 1) 小鼠 AP 发病后不久，血清 RNLS 迅速下降模型和人体； 2）RNLS的基因缺失增加了实验性急性小鼠的严重程度胰腺炎; 3) 重组 RNLS (rRNLS) 降低离体小鼠的胰腺炎反应胰腺腺泡细胞； 4) 外源性rRNLS显着降低小鼠急性发作的严重程度作为预处理或发病后两小时给予体内胰腺炎。最初的研究表明，RNLS 衍生肽可减少多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 衍生肽并将其与 rRNLS 的功效进行比较减少 AP 伤害。这些肽可能比 rRNLS 具有易于制造的优势以及更强的专利地位。将根据以下具体目标选择和审查先导药物： 1) 将比较 RNLS 和 RNLS 衍生的较小肽/优先考虑它们在减少分离的小鼠胰腺腺泡细胞的胰腺炎反应。 2) rRNLS对AP严重程度的影响目标 1 中确定的两种最有效的肽将在两只实验小鼠中进行检查模型：由高剂量雨蛙素诱导的轻度AP模型和由高剂量的雨蛙素诱导的重度AP模型腹腔内注射酒精和脂肪酸。为了进一步反映临床治疗场景，有效性在损伤发生前或损伤发生后给予 rRNLS 或相关肽时，将进行检查疾病。此外，AP 的传统生化测量将与 RNLS 水平以及疼痛是急性胰腺炎的主要症状。如果成功，该项目将为后期阶段做好准备一种新颖且设计合理的治疗方法的开发和临床研究。基于实力初步数据和证据表明，这种新的生存途径对于这两种疾病都具有根本性的重要意义小鼠模型和人类疾病，RNLS 疗法在以下方面具有非常高的有效潜力：预防或治疗AP。