Triterpenoid Modulators of Inflammatory Driven Carcinogenesis

炎症驱动的致癌作用的三萜调节剂

基本信息

批准号：
8083600
负责人：
Gregory P Tochtrop
金额：
$ 30.02万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8083600
关键词：
2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid Analgesics Anti-Inflammatory Agents Anti-inflammatory Asians Azoxymethane Back Biological Biological Factors Cardiovascular system Categories Cells Chemicals Chemistry Chemoprevention Chemopreventive Agent Chronic Clinical Clinical Research Colon Carcinoma Colorectal Cancer Communication Couples Cyclization DNA Sequence Rearrangement Disease Dissection Effectiveness Enzymes Epidemiology Epigenetic Process Epithelial Epithelial Cells Epithelium Event FVB Mouse Gastrointestinal tract structure Genes Human Immune Immune Cell Activation In Vitro Inflammation Inflammation Mediators Inflammatory Lead Link Lymphocyte MADH4 gene Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of gastrointestinal tract Mediating Medicine Modeling Molecular Mus Nerve Degeneration Non-Steroidal Anti-Inflammatory Agents Oleanolic Acid Oncogenic Organic Synthesis Pathway interactions Phase Physiology Plants Pre-Clinical Model Predisposition Prevention Production Property Research Personnel Series Signal Transduction Skeleton Source Stress Structure-Activity Relationship System T-Lymphocyte Testing Traditional Medicine Tumor Suppressor Proteins Work Xenograft procedure antimicrobial cancer prevention carcinogenesis cyclooxygenase 2 cytokine gastrointestinal human NOS2A protein in vitro Assay in vivo innovation interest macrophage mouse model novel oleanane response scaffold skeletal tumor

项目摘要

DESCRIPTION (provided by applicant): An extensive body of work supports a fundamental link between inflammation and a number of diseases, particularly cancer. Synthetic oleanane triterpenoids have been shown in preclinical models to be potent in the prevention of cancer driven by chronic inflammation. A central premise of the proposed work is that the oleanane triterpenoids are representative of a much larger class of anti-inflammatory/anti-cancer triterpenoids. We hypothesize that exploration of diverse triterpenoids, will allow a careful dissection of the molecular pathways behind triterpenoid chemoprevention, and will define novel classes of potent and effective cancer chemopreventive agents. To study the chemical space around the triterpenoids we will use two approaches including: 1) a novel oxidative cleavage and skeletal rearrangement; and 2) an innovative natural product isolation strategy to identify novel triterpenoids. These molecules will then be evaluated in vitro for their ability to suppress expression of key inflammatory mediators, and in vivo for their ability to suppress progression of gastrointestinal carcinogenesis in a system that couples immune mediated induction of oncogenic signaling intermediates with loss of expression of important tumor suppressor pathways. PUBLIC HEALTH RELEVANCE: This project represents a collaborative endeavor between a two investigators interested in triterpenoids as cancer chemopreventives. The described aims will synthesize and isolate known and novel triterpenoids from traditional medicine sources to be tested as chemopreventives in inflammation driven models of carcinogenesis.

描述（由申请人提供）：广泛的工作支持炎症与多种疾病，尤其是癌症之间的基本联系。在临床前模型中已显示合成的三萜类化合物三萜类化合物在预防慢性炎症驱动的癌症方面有效。拟议的工作的一个中心前提是，三萜的三萜类化合物代表了更大类别的抗炎/抗癌三萜类化合物。我们假设探索各种三萜类化合物，将仔细解剖三萜类化学预防后的分子途径，并将定义新型有效且有效的癌症化学预防剂的新型类型。为了研究三萜周围的化学空间，我们将使用两种方法，包括：1）一种新型的氧化裂解和骨骼重排； 2）一种创新的天然产品隔离策略，以识别新型三萜。然后，将在体外评估这些分子，以抑制关键炎症介质表达的能力，并在体内抑制抑制胃肠道致癌的进展的能力，该系统结合了免疫介导的致癌信号诱导的诱导与重要肿瘤抑制途径的表达的诱导致癌信号中间体。公共卫生相关性：该项目代表了两个对三烯型兴趣作为癌症化学预防的研究者之间的合作努力。所描述的目的将从传统的医学来源中合成并分离已知和新颖的三萜类化合物，以在炎症驱动的癌变模型中被测试为化学预防剂。