Novel Intervention for Colitis

结肠炎的新型干预措施

• 批准号: 7218881
• 负责人: MICHAEL PETER VITEK
• 金额: $ 27.93万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218881
• 关键词: Abdominal Pain; Acute; Adrenal Cortex Hormones; Adverse effects; Affect; Allergic; American; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Arginine; Automobile Driving; Blood; Brain; Brain Diseases; Cells; Chronic; Citrobacter rodentium; Clinical; Colitis; Collaborations; Colon; Condition; Crohn' s disease; Data; Dextran Sulfate; Diabetes Mellitus; Diarrhea; Diet; Disease; Disorder by Site; Dose; Enzymes; Epithelial Cells; Equilibrium; Family; Fistula; Gastrointestinal Diseases; Generations; Genus Cola; Grant; Human; Immunology; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intervention; Intestines; Laboratories; Link; Malignant Neoplasms; Measures; Mediator of activation protein; Metabolism; Modality; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mucositis; Multiple Sclerosis; Mus; Muscle Cramp; Natural Immunity; Nitric Oxide; Nitric Oxide Synthase; Obstruction; One-Step dentin bonding system; Onset of illness; Ornithine Decarboxylase; Outcome; Outcome Measure; Pancreatitis; Pathway interactions; Patients; Peptides; Perforation; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Play; Polyamines; Production; Proteins; Publishing; Quality of life; Regulation; Risk; Role; Score; Sepsis; Severities; Severity of illness; Sodium; Sodium Dextran Sulfate; Spinal Cord; Symptoms; Systemic infection; Therapeutic; Tissues; Treatment Protocols; Ulcerative Colitis; Universities; Wild Type Mouse; Work; analog; arginase; base; bone loss; clinically relevant; cytokine; gastrointestinal; human disease; improved; in vivo; infliximab; inhibitor/antagonist; innovation; interest; macrophage; mimetics; mouse model; novel; novel therapeutics; receptor binding; research study; response; small molecule; symposium; trait

DESCRIPTION (provided by applicant): Novel Intervention for Colitis The scope of the current proposal is to determine whether administration of an apoE mimetic peptide, COG112, improves clinical, histological and inflammatory outcomes in clinically relevant paradigms of colitis. Specifically, we will employ the acute Citrobacter rodentium (C. rodentium) model, an acute Dextran Sulfate Sodium (DSS) model and a chronic DSS model of colitis. We will also define whether there is a dose-dependent response to treatment with COG112 in these models of human disease. This course of experiments has the potential to represent a novel therapeutic strategy for a difficult gastrointestinal disease in which adequate treatment strategies do not currently exist. Specific Aim 1: Using a C. rodentium-infectious model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 2: Using a DSS model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 3: Using a DSS model of chronic colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Novel Intervention for Colitis: Inflammatory Bowel Disease (IBD), more commonly known as Crohn's disease and ulcerative colitis, affects approximately 1 million Americans with inflammation of the intestines, abdominal pain, cramping and diarrhea. These symptoms vary in severity, but are often debilitating for patients to the extent that they greatly alter their quality of life. We have found that clinical and histological scores of IBD are less when the levels of small molecules known as polyamines are increased. To increase polyamine levels, one needs to increase the amount of arginine, an amino acid derived from our diets, that is converted to polyamines through the action of the arginase/ornithine decarboxylase pathway. We have found a novel drug, COG112, can stimulate this arginase activity. Thus, mouse models of colitis treated with COG112 should have less disease than their untreated counterparts. So we propose to directly measure whether COG112 will exacerbate or ameliorate colitis in mouse models.

描述(由申请人提供)：结肠炎的新干预措施目前的建议范围是确定给予载脂蛋白E模拟多肽COG112是否能改善临床相关类型的结肠炎的临床、组织学和炎症结果。具体地说，我们将采用急性罗氏柠檬酸杆菌(C.rolinum)模型、急性葡聚糖硫酸钠(DSS)模型和结肠炎慢性DSS模型。我们还将确定在这些人类疾病模型中是否存在对COG112治疗的剂量依赖性反应。这一实验过程有可能代表一种新的治疗策略，用于治疗目前尚不存在适当治疗策略的难治性胃肠道疾病。具体目标1：使用轮状念珠菌感染的急性结肠炎模型，使用临床结果指标、组织结果指标和一组代表性炎症介质的指标来衡量不同剂量的COG112治疗的反应。具体目标2：使用DSS急性结肠炎模型，使用临床结果指标、组织结果指标和一组代表性炎症介质的指标来衡量不同剂量COG112治疗的反应。具体目标3：使用DSS慢性结肠炎模型，使用临床结果指标、组织结果指标和一组代表性炎症介质的指标来衡量不同剂量COG112治疗的反应。结肠炎的新干预措施：炎症性肠病(IBD)，通常被称为克罗恩病和溃疡性结肠炎，影响着大约100万美国人的肠道炎症、腹痛、抽筋和腹泻。这些症状的严重程度各不相同，但往往会使患者虚弱到极大地改变他们的生活质量的程度。我们发现，当称为多胺的小分子水平增加时，IBD的临床和组织学评分较低。为了增加多胺水平，人们需要增加精氨酸的数量，精氨酸是一种来自我们饮食的氨基酸，通过精氨酸酶/鸟氨酸脱羧酶途径的作用转化为多胺。我们发现了一种新药，COG112，可以刺激这种精氨酸酶的活性。因此，使用COG112治疗的结肠炎小鼠模型的疾病应该比未治疗的小鼠少。因此，我们建议直接测量COG112是否会加重或改善小鼠模型的结肠炎。