Novel Intervention for Colitis

描述（由申请人提供）：结肠炎的新干预当前提议的范围是确定施用apoE模拟肽COG 112是否改善结肠炎临床相关范例中的临床、组织学和炎症结果。具体而言，我们将采用急性啮齿类柠檬酸杆菌（C。啮齿动物）模型、结肠炎的急性葡聚糖硫酸钠（DSS）模型和慢性DSS模型。我们还将确定在这些人类疾病模型中是否存在对COG 112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，为困难的胃肠道疾病，其中充分的治疗策略目前还不存在。具体目标1：使用C。急性结肠炎的啮齿动物感染模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对用不同剂量的COG 112治疗的响应。具体目标二：使用急性结肠炎的DSS模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对用不同剂量的COG 112治疗的响应。具体目标3：使用慢性结肠炎的DSS模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对用不同剂量的COG 112治疗的响应。结肠炎的新干预措施：炎症性肠病（IBD），更常见的是克罗恩病和溃疡性结肠炎，影响大约100万美国人的肠道炎症，腹痛，痉挛和腹泻。这些症状的严重程度各不相同，但通常会使患者衰弱，从而大大改变他们的生活质量。我们已经发现，当被称为多胺的小分子水平增加时，IBD的临床和组织学评分降低。为了增加多胺水平，需要增加精氨酸的量，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。我们已经发现一种新的药物，COG 112，可以刺激这种酶的活性。因此，用COG 112治疗的结肠炎小鼠模型的疾病应该比未治疗的小鼠模型少。因此，我们建议直接测量COG 112是否会加重或改善小鼠模型中的结肠炎。

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.