Curcumin and chemoprevention of H. pylori-associated gastric carcinogenesis

姜黄素和幽门螺杆菌相关胃癌的化学预防

• 批准号: 8353168
• 负责人: Rupesh Chaturvedi
• 金额: $ 12.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353168
• 关键词: Acute; African; Alternative Medicine; Alzheimer' s Disease; Analytical Biochemistry; Animal Model; Animals; Antibiotic Therapy; Apoptosis; Atrophic Gastritis; Award; Bacteria; Biological; Biological Availability; Biological Factors; Biological Process; Biological Response Modifiers; C57BL/6 Mouse; Cancer Biology; Cancer Etiology; Caspase; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic Gastritis; Clinical; Coculture Techniques; Colorectal Cancer; Consumption; Country; Curcumin; DNA; DNA Damage; Diet; Disease; Educational workshop; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Exhibits; Figs - dietary; Food; Funding; Gastric Adenocarcinoma; Gastrins; Gastritis; Gastrointestinal Diseases; Generations; Genetic Predisposition to Disease; Gerbils; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; High Prevalence; Human; Immune; Immune response; Immunology; Immunosuppressive Agents; In Vitro; Incidence; India; Infection; Inflammatory Bowel Diseases; Informatics; Injury; Insulin; Interleukin-10; Interleukin-12; Intestinal Metaplasia; Laboratories; Lead; Link; Lymphocyte Activation; MAPK14 gene; Medicine; Mentors; Mentorship; Microbiology; Modeling; Molecular; Mus; Mutation; Neonatal; Outcome; Pathogenesis; Pathology; Peptic Ulcer; Phenotype; Phylogenetic Analysis; Physicians; Plants; Population; Positioning Attribute; Postdoctoral Fellow; Prevalence; Prevention; Prevention strategy; Principal Investigator; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Rest; Risk Factors; Scientist; Signal Transduction; Stomach; Stomach Carcinoma; System; TNFRSF5 gene; Testing; Time; Training; Tumeric; ayurveda; base; cancer risk; carcinogenesis; career; cytokine; experience; graduate student; in vivo; instructor; macrophage; malignant stomach neoplasm; meetings; mouse model; novel; prevent; professor; response; tool

DESCRIPTION (provided by applicant): The overarching goal of this award is to provide comprehensive training to prepare the principal investigator for an independently-funded research career, focused on Complimentary and Alternative Medicine (CAM) natural products and their effect on clinical outcomes of gastroenterological diseases. I am a Research Instructor with extensive experience in the immunopathogenesis of H. pylori. My near-term goal is to gain additional expertise in analytical biochemistry, an essential tool for performing research with natural products. This award will allow me to meet this goal with formal graduate-level coursework; workshops in separation, analysis, and informatics; and protected time for five years of mentored research. My mentor is Keith T. Wilson, MD, Professor of Medicine, Cancer Biology, and Pathology, Microbiology, and Immunology, who has a well- established track record of high impact mucosal immunology research related to H. pylori and inflammatory bowel disease. Dr. Wilson has successfully mentored graduate students, post-doctoral fellows, and physician- scientists. The strong mentorship, additional training, and environment detailed in this application will position me to reach my ultimate objective of becoming an independent investigator in the field of CAM natural products. This application will facilitate understanding f the molecular mechanisms underlying the action of curcumin in protecting the host from H. pylori infection and associated pathology. H. pylori is a Gram-negative bacterium that causes chronic gastritis, peptic ulcers, and gastric cancer. Gastric adenocarcinoma is the second leading cause of cancer-related death worldwide and H. pylori infection is its strongest known risk factor. However, in some disparate parts of the world research has found very low rates of gastric cancer despite high H. pylori prevalence; these phenomena have been termed the African, Colombian, and Indian enigmas. The African enigma has been attributed to parasitic co-infection in humans and recently our laboratory has demonstrated that the geographical origin of the bacteria may also be a basis for the Colombian enigma. Diet has been postulated as a possible explanation for the Indian enigma. Curcumin, a secondary metabolite of the plant turmeric, is a common food ingredient in India and its consumption (40-200 mg/day) has been linked to decreased incidence of colorectal cancer and Alzheimer's disease. H. pylori infection induces a strong macrophage (Mac)-associated innate immune response and an inappropriate Th1-biased adaptive immune response that contributes to disease pathogenesis. In this application we hypothesize that curcumin polarizes H. pylori activated Macs to a tolerant regulatory phenotype in a NF-kB1 (p105/p50)-dependent manner. Tolerance may lead to persistence of H. pylori, and thus long-term interaction of bacteria and epithelial cells that induces DNA damage and resulting mutations. However, in the application, we will test the hypothesis that curcumin specifically induces apoptosis in gastric epithelial cells with DNA damage and will thus have an overall effect of decreasing cancer risk. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a Gram-negative bacterium causing chronic gastritis, peptic ulcers, and gastric cancer. Antibiotic treatment can be costly and often fails to eradicate the infection. In the proposed application we seek to define new strategies for amelioration and prevention of Helicobacter pylori-induced diseases with curcumin.

描述（由申请人提供）：该奖项的总体目标是提供全面的培训，帮助主要研究者为独立资助的研究生涯做好准备，重点关注补充和替代医学 (CAM) 天然产品及其对胃肠病学临床结果的影响疾病。我是一名研究讲师，在幽门螺杆菌免疫发病机制方面拥有丰富的经验。我的近期目标是获得分析生物化学方面的更多专业知识，这是进行天然产品研究的重要工具。该奖项将使我能够通过正式的研究生水平课程来实现这一目标；分离、分析和信息学研讨会；并保护五年指导研究的时间。我的导师是基思·T·威尔逊 (Keith T. Wilson) 医学博士，他是医学、癌症生物学、病理学、微生物学和免疫学教授，在与幽门螺杆菌和炎症性肠病相关的高影响粘膜免疫学研究方面拥有良好的记录。威尔逊博士成功地指导了研究生、博士后研究员和医师科学家。本节详细介绍了强有力的指导、额外培训和环境 申请将使我能够实现成为 CAM 天然产品领域的独立研究者的最终目标。 该应用将有助于理解姜黄素保护宿主免受幽门螺杆菌感染和相关病理学作用的分子机制。幽门螺杆菌是一种革兰氏阴性细菌，可引起慢性胃炎、消化性溃疡和胃癌。胃腺癌是全球癌症相关死亡的第二大原因，幽门螺杆菌感染是已知的最强危险因素。然而，在世界一些不同地区，研究发现，尽管幽门螺杆菌患病率很高，但胃癌的发病率却很低。这些现象被称为非洲、哥伦比亚和印度的谜团。非洲之谜被归因于人类的寄生虫双重感染，最近我们的实验室证明细菌的地理起源也可能是哥伦比亚之谜的基础。饮食被认为是印度之谜的一个可能解释。姜黄素是植物姜黄的次生代谢产物，是印度常见的食品成分，其摄入量（40-200 毫克/天）与降低结直肠癌和阿尔茨海默病的发病率有关。幽门螺杆菌感染会诱导强烈的巨噬细胞 (Mac) 相关先天免疫反应和不适当的偏向 Th1 的适应性免疫反应，从而导致疾病发病机制。在此应用中，我们假设姜黄素以 NF-kB1 (p105/p50) 依赖性方式将幽门螺杆菌激活的 Mac 极化为耐受的调节表型。耐受性可能导致幽门螺杆菌持续存在，从而导致细菌和上皮细胞的长期相互作用，从而诱导 DNA 损伤并导致突变。然而，在本申请中，我们将测试以下假设：姜黄素特异性诱导 DNA 损伤的胃上皮细胞凋亡，从而具有降低癌症风险的总体效果。 公众健康相关性：幽门螺杆菌是一种革兰氏阴性细菌，可引起慢性胃炎、消化性溃疡和胃癌。抗生素治疗费用昂贵，而且常常无法根除感染。在拟议的应用中，我们寻求确定姜黄素改善和预防幽门螺杆菌引起的疾病的新策略。