Role of STAT3 in the pathogenesis of Inflammatory Bowel Disease

STAT3在炎症性肠病发病机制中的作用

• 批准号: 8443096
• 负责人: PREMA ROBINSON
• 金额: $ 7.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443096
• 关键词: Abdominal Pain; Acute; Adrenal Cortex Hormones; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Attenuated; Body Weight decreased; CD4 Positive T Lymphocytes; Cell Nucleus; Cell surface; Cells; Chronic; Colitis; Colon; Colorectal Cancer; Crohn' s disease; Dependency; Development; Diarrhea; Disease; Feces; Future; Gastrointestinal Hemorrhage; Genes; Heart; Hemorrhage; Hemorrhagic Shock; Human; Immunosuppression; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Obstruction; Intestines; Knock-in Mouse; Knock-out; Lead; Length; Life; Lipopolysaccharides; Liver; Lung; Malnutrition; Mediating; Messenger RNA; Mus; Opportunistic Infections; Pathogenesis; Persons; Play; Pre-Clinical Model; Prevalence; Prevention; Production; Protein Isoforms; RNA Splicing; Resistance; Risk; Role; STAT3 gene; Severity of illness; Signal Transduction; Small Intestines; Sodium Dextran Sulfate; Stat3 protein; Sulfonic Acids; T-Lymphocyte; Transgenic Organisms; Trinitrobenzenes; Ulcerative Colitis; United States; chemokine; clinical application; cytokine; human tissue; inhibitor/antagonist; innovation; mortality; mouse model; novel; novel strategies; peptide hormone; prevent; public health relevance; rectal; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is an idiopathic disease of the colon and small intestine. The major types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). An estimated 1.4 million persons in the United States suffer from IBD. IBD causes severe diarrhea, abdominal pain and increases the risk of colorectal cancer. Importantly, there is no cure for IBD. Signal transducer and activator of transcription (Stat) 3 ha been shown to play a pathogenic role in mice models of IBD. Increased levels of activated Stat3 directly correlated with the degree of intestinal inflammation in humans with IBD. There are two isoforms of Stat3 (¿/p92 and ¿/p83). Mice expressing only Stat3¿ are hyper-responsive to bacterial LPS challenge and are resistant to hemorrhagic shock-induced apoptosis of parenchymal cells within the heart, lung, and liver suggesting that Stat3¿ attenuates inflammatory and anti-apoptotic responses mediated by Stat3¿. We previously developed a potent, small-molecule Stat3 inhibitor (C188-9) that is selective for Stat3¿ vs. Stat3¿. In preliminary studies, we demonstrated that C188-9 almost completely prevents dextran sodium sulphate (DSS)-induced colitis in mice. In the current proposal, we will use C188-9 and transgenic Stat3¿ mice to interrogate the hypothesis that Stat3¿ contributes to the pathogenesis of IBD and to establish proof-of-principle that IBD can be treated using selective pharmacological targeting of Stat3¿. We have formulated 2 tightly focused aims to examine this hypothesis. Specific aim 1: To determine if IBD can be treated with C188-9, a small-molecule inhibitor of Stat3 that selectively targets Stat3¿. We will determine if C188-9 is of benefit in 2 preclinical models of chronic IBD-IBD induced by DSS, which mimics UC, and IBD induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics CD. Endpoints that will be examined include mortality rate, weight loss, rectal bleeding, stool consistency, colon length and extent of colonic inflammation (as determined by histopathological assessment). We will also examine if the mechanism by which C188-9 inhibits the pathogenesis of IBD is through decreasing the production of proinflammatory cytokines and chemokines by immunocytes and/or through increased apoptosis of pathogenic CD4+T-cells. Specific aim 2: To determine the contribution of Stat3¿ to the pathogenesis of IBD. We will subject transgenic Stat3¿ knock-in/Stat¿-deficient mice and their littermate WT controls to DSS- and TNBS-induced colitis and compare the severity of disease manifestations, levels of cytokines and chemokines and T-cell apoptosis as outlined in Aim 1. This proposal will provide support for the hypothesis that Stat3, particularly Stat3¿, contributes to the pathogenesis of IBD and that targeting Stat3 with a small molecule inhibitor that is selective for Stat3¿ is a novel and effective approach to IBD treatment.

描述（由申请人提供）：炎症性肠病（IBD）是一种结肠和小肠的特发性疾病。IBD的主要类型是克罗恩病（CD）和溃疡性结肠炎（UC）。据估计，美国有140万人患有IBD。IBD会导致严重的腹泻、腹痛，并增加患结肠直肠癌的风险。重要的是，目前还没有治愈IBD的方法。信号换能器和转录激活因子（Stat） 3已被证明在小鼠IBD模型中起致病作用。激活Stat3水平的升高与IBD患者肠道炎症程度直接相关。Stat3有两个同工异构体（¿/p92和¿/p83）。仅表达Stat3¿的小鼠对细菌LPS的攻击反应非常敏感，并且对出血性休克诱导的心脏、肺和肝脏实质细胞凋亡具有抗性，这表明Stat3¿可以减轻由Stat3¿介导的炎症和抗凋亡反应。我们之前开发了一种有效的小分子Stat3抑制剂（C188-9），它对Stat3¿与Stat3¿具有选择性。在初步研究中，我们证明C188-9几乎完全阻止右旋糖酐硫酸钠（DSS）诱导的小鼠结肠炎。在目前的提案中，我们将使用C188-9和转基因Stat3¿小鼠来质疑Stat3¿参与IBD发病机制的假设，并建立可以通过选择性靶向Stat3¿治疗IBD的原理证明。我们制定了两个紧密聚焦的目标来检验这一假设。具体目的1：确定是否可以用C188-9治疗IBD， C188-9是一种选择性靶向Stat3¿的小分子Stat3抑制剂。我们将确定C188-9是否对两种临床前模型的慢性IBD-IBD有益处，分别是由DSS（模拟UC）和2,4,6 -三硝基苯磺酸（TNBS）（模拟CD）诱导的IBD。将检查的终点包括死亡率、体重减轻、直肠出血、粪便一致性、结肠长度和程度