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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.

项目总结/文摘