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：
8403947
负责人：
Gregory P Tochtrop
金额：
$ 29.74万
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/8403947
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 public health relevance 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.

描述（由申请人提供）：大量工作支持炎症与许多疾病（特别是癌症）之间的基本联系。临床前模型已证明合成齐墩果烷三萜类化合物可有效预防慢性炎症引起的癌症。所提出的工作的一个中心前提是齐墩果烷三萜类化合物是一大类抗炎/抗癌三萜类化合物的代表。我们假设对不同三萜类化合物的探索将允许仔细剖析三萜类化合物化学预防背后的分子途径，并将定义新类别的强效且有效的癌症化学预防剂。为了研究三萜类化合物周围的化学空间，我们将使用两种方法，包括：1）新型氧化裂解和骨架重排； 2）创新的天然产物分离策略来鉴定新型三萜类化合物。然后，将在体外评估这些分子抑制关键炎症介质表达的能力，并在体内评估其在将免疫介导的致癌信号中间体诱导与重要肿瘤表达丧失相结合的系统中抑制胃肠道癌发生进展的能力。抑制途径。