Inflammatory Bowel Disease: A Novel Therapeutic Approach

炎症性肠病：一种新的治疗方法

• 批准号: 7564040
• 负责人: Pawel R Kiela
• 金额: $ 26.66万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564040
• 关键词: Adolescent; Adult; Adverse effects; Affect; American; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biochemical; Body Weight decreased; Botanicals; Cell Line; Cells; Chemicals; Chemopreventive Agent; Child; Childhood; Chronic; Clinical Trials; Colitis; Colon; Crohn' s disease; Curcuma longa; Curcumin; Data; Defensins; Disease; Dose; Economic Burden; Effectiveness; Environmental Risk Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Evaluation; Exhibits; Future; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genus Cola; Goals; Homologous Gene; Human; IL8 gene; Immune; Immune response; Immune system; Inbred BALB C Mice; Individual; Induction of Apoptosis; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Investigation; Knock-out; Knowledge; Lamina Propria; Light; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Microarray Analysis; Modality; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphology; Mouse Strains; Mus; NF-kappa B; Nature; Pathogenesis; Patients; Peptides; Population; Powder dose form; Predisposition; Prevalence; Preventive; Property; Protein Kinase C; Protein Tyrosine Kinase; Publishing; Reactive Oxygen Species; Relapse; Report (account); Reporting; Research; Rhizome; Role; SJL/J Mouse; Signal Transduction; Source; Spices; Survival Rate; System; T-Lymphocyte; Technology; Testing; Therapeutic; Toxic effect; Tumeric; Ulcerative Colitis; United States; alternative treatment; antimicrobial; base; chemical carcinogenesis; chemokine; comparative; cost; cryptdin; dietary supplements; effective therapy; feeding; gene induction; genome-wide; improved; inhibitor/antagonist; insight; interest; macrophage; microorganism antigen; mouse model; neoplastic cell; novel; novel therapeutic intervention; protective effect; psychosocial; receptor; response; transcription factor

DESCRIPTION (provided by applicant): Ulcerative Colitis (UC) and Crohn's Disease (CD) are chronic, relapsing inflammatory disorders of the gastrointestinal tract, collectively known as Inflammatory Bowel Disease (IBD). The cause of IBD, which in U.S. affects an estimated 1 million individuals, including children and adolescents, remains largely unknown. Pathogenesis of IBD is most commonly viewed as an effect of an aberrant immune response against ubiquitous, non-pathogenic microbial antigens. In view of traditional and novel treatments of IBD, their side effects and high cost prompt investigations into new, alternative treatment modalities. One such alternative is a long-known anti-inflammatory and chemopreventive component of turmeric spice, curcumin, which was only recently reported to significantly attenuate or ameliorate experimentally induced colitis in mice. Curcumin is poorly absorbed, and extensively metabolized in the gastrointestinal tract, which may account for the reported lack of toxicity. The goal of this proposed project is to investigate the mechanism of curcumin's protective action against colitis in further detail and to provide a sufficient scientific background for clinical trials in both pediatric and adult IBD patients. This will be accomplished by studying the effectiveness of dietary curcumin in immune-based mouse models of colitis. IL-10-/- and TCRalpha-/- mice with different propensities for immune dysregulation (Th1- and Th2-dominated, respectively) will be used. Macroscopic, morphological, and biochemical evaluation will be followed by comparative genome-wide microarray analyses of gene expression profiles in colonic epithelial and immune cells in order to gain further insight into molecular targets of curcumin and its mechanism of action. Also, epithelial metabolism of curcumin will be qualitatively and quantitatively analyzed in colonocytes isolated from control mice and from mice with established differentially polarized inflammation with the help of HPLC/LC-MS technology. The compounds identified as novel metabolites of curcumin will be evaluated for anti-inflammatory activity utilizing established models of mouse macrophages (RAW264.7) and colonocytes (YAMC cells). To shed more light into novel mechanisms of curcumin action in the intestine, its effects on expression of colonic antibacterial cryptdin -related peptides will be investigated. Also, we will describe its mechanism of action on identified uniquely regulated genes such as LPS-mediated early induction of MIP-2 (murine homologue of IL-8) gene transcription. In summary, the proposed project will provide novel information about the mechanism of curcumin's action in IBD, about its molecular targets in differently polarized T-cell mediated inflammation as well as about the molecular forms of the active compound in the healthy and inflamed colon.

描述（由申请人提供）：溃疡性结肠炎（UC）和克罗恩病（CD）是胃肠道的慢性、复发性炎症性疾病，统称为炎症性肠病（IBD）。在美国，IBD 影响了大约 100 万人，其中包括儿童和青少年，但其病因在很大程度上仍不清楚。 IBD 的发病机制通常被认为是针对普遍存在的非致病性微生物抗原的异常免疫反应的结果。鉴于 IBD 的传统和新型治疗方法，其副作用和高成本促使人们研究新的替代治疗方式。其中一种替代品是姜黄香料中一种众所周知的抗炎和化学预防成分——姜黄素，直到最近才被报道可以显着减轻或改善实验诱发的小鼠结肠炎。姜黄素吸收不良，并在胃肠道中广泛代谢，这可能是报道中缺乏毒性的原因。该项目的目标是更详细地研究姜黄素对结肠炎的保护作用机制，并为儿童和成人 IBD 患者的临床试验提供足够的科学背景。这将通过研究膳食姜黄素在基于免疫的小鼠结肠炎模型中的有效性来实现。将使用具有不同免疫失调倾向（分别以 Th1 和 Th2 为主）的 IL-10-/- 和 TCRalpha-/- 小鼠。在宏观、形态学和生化评估之后，将对结肠上皮细胞和免疫细胞的基因表达谱进行比较全基因组微阵列分析，以进一步了解姜黄素的分子靶点及其作用机制。此外，借助 HPLC/LC-MS 技术，将在从对照小鼠和已建立差异极化炎症的小鼠中分离的结肠细胞中对姜黄素的上皮代谢进行定性和定量分析。将利用已建立的小鼠巨噬细胞（RAW264.7）和结肠细胞（YAMC 细胞）模型来评估被鉴定为姜黄素新型代谢物的化合物的抗炎活性。为了更多地了解姜黄素在肠道中作用的新机制，将研究其对结肠抗菌隐蛋白相关肽表达的影响。此外，我们还将描述其对已识别的独特调控基因的作用机制，例如 LPS 介导的 MIP-2（IL-8 的小鼠同源物）基因转录的早期诱导。总之，拟议的项目将提供关于姜黄素在 IBD 中的作用机制、不同极化 T 细胞介导的炎症中的分子靶标以及健康和发炎结肠中活性化合物的分子形式的新信息。