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

基本信息

批准号：
8517590
负责人：
Rupesh Chaturvedi
金额：
$ 12.22万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517590
关键词：
Acute African Alternative Medicine Alzheimer&apos 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

Acute African Alternative Medicine Alzheimer&apos 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

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项目摘要

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.

描述（由申请人提供）：该奖项的总体目标是提供全面的培训，以使主要研究人员为独立资助的研究生涯做好准备，专注于免费和替代医学（CAM）天然产品及其对胃肠病学疾病临床结果的影响。我是一名研究指导员，在幽门螺杆菌的免疫发作中拥有丰富的经验。我的近期目标是获得分析生物化学方面的更多专业知识，这是对天然产品进行研究的重要工具。该奖项将使我能够通过正式的研究生级课程实现这一目标；分离，分析和信息学的讲习班；并保护了五年的指导研究时间。我的导师是医学，癌症生物学和病理学，微生物学和免疫学教授基思·威尔逊（Keith T.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。强大的指导，额外的培训和环境详细介绍了应用将使我达到成为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在保护宿主免受幽门螺杆菌感染和相关病理中的作用的分子机制。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。胃腺癌是全球与癌症相关死亡的第二大原因，幽门螺杆菌感染是其最强的已知危险因素。但是，在世界的某些地区，研究发现，尽管幽门螺杆菌患病率很高，但胃癌的发生率非常低。这些现象已被称为非洲，哥伦比亚人和印度谜团。非洲谜团归因于人类的寄生共同感染，最近我们的实验室表明，细菌的地理起源也可能是哥伦比亚谜的基础。饮食已被认为是印度谜的可能解释。姜黄素是植物姜黄的继发代谢物，是印度的一种常见食品成分，其消费量（40-200 mg/天）与结直肠癌和阿尔茨海默氏病的发病率降低有关。幽门螺杆菌感染诱导强大的巨噬细胞（MAC）相关的先天免疫反应和不适当的Th1偏向适应性免疫反应，这有助于疾病发病机理。在此应用中，我们假设姜黄素以NF-KB1（p105/p50）依赖性方式使幽门螺杆菌激活的MACS激活了MACS。耐受性可能导致幽门螺杆菌的持久性，从而导致细菌和上皮细胞的长期相互作用，从而诱导DNA损伤并产生突变。但是，在应用中，我们将检验以下假设：姜黄素特异性地诱导胃皮细胞中的DNA损伤凋亡，因此将产生降低癌症风险的总体作用。