Etiological Studies of Gastric Carcinoma

胃癌的病因学研究

• 批准号: 9095247
• 负责人: PELAYO none CORREA
• 金额: $ 104.4万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095247
• 关键词: Academic Medical Centers; Adverse effects; Affect; Andean; Antibiotic Therapy; Antibiotics; Atrophic; Bacteria; Bioinformatics; Biological Markers; Cancer Biology; Cancer Center; Cancer Etiology; Cancerous; Carcinogens; Central America; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Collaborations; Colombia; Colombian; Complex; Cross-Sectional Studies; DNA Damage; Data; Developing Countries; Digestive System Disorders; Disease; Disease Progression; ERBB2 gene; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epidemiology; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Etiology; Event; Financial Support; Foxes; Funding; Gastric Adenocarcinoma; Gastroenterology; Genes; Genetic; Genetic Variation; Genomics; Goals; Health; Helicobacter pylori; Helminths; High Prevalence; High-Risk Cancer; Hispanics; Histopathology; Human; Human Genetics; Human Resources; Immigrant; Immune; Immune response; Immunologics; Immunology; Individual; Infection; Infectious Agent; Inflammation; Institutes; Interdisciplinary Study; International; Intervention; Intestinal Metaplasia; Investigation; Investments; Latin America; Lead; Lesion; Link; Malignant Neoplasms; Methylation; Microbe; Microbiology; Molecular; Molecular Epidemiology; Molecular Profiling; Parasites; Parasitic infection; Pathology; Pathway interactions; Patients; Persons; Pharmacology; Phosphorylation; Physiology; Polyamines; Population; Positioning Attribute; Premalignant; Prevention program; Prevention strategy; Program Research Project Grants; Proteomics; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; Seminal; Site; Spermine; Staging; Stomach; Stomach Carcinoma; Stomach Diseases; Stratification; Translational Research; United States; United States National Institutes of Health; Variant; Virulence Factors; Work; World Health Organization; anticancer research; antimicrobial; bacterial genetics; base; cancer risk; carcinogenesis; cohort; follow-up; gastric cancer prevention; global health; gut microbiota; high risk; human subject; improved; innovation; insight; low and middle-income countries; malignant stomach neoplasm; microbiota; molecular imaging; mortality; neoplastic; novel; novel strategies; operation; oxidation; oxidative DNA damage; pathogen; personalized medicine; polyamine oxidase; prevent; programs; promoter; response; square foot; study population; tumor progression

DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the leading infection-associated cancer and third most common cause of global cancer mortality. Helicobacter pylori infects over half of the world's population and up to 85% of persons residing in developing nations, yet prevention programs and biomarkers are lacking to identify high risk strains and to manage patients with precancerous lesions. This Program Project Grant has made seminal contributions to gastric cancer research by utilizing extensive and well-organized infrastructures in Latin America, organized around a unique long-term cohort of human subjects from a former chemoprevention trial in the high cancer risk Andean region of Colombia. Central accomplishments include discoveries related to: 1) high risk (mountain) vs. low risk (coastal) cancer risk regions; 2) H. pylori strain phylogeographic origin and genetic mismatch between human hosts and the infecting strains that are directly linked with disease progression; 3) important disease modifiers including the gastric microbiota and concurrent parasitic infection; 4) a causal role for polyamines and specifically the oxidation of spermine by spermine oxidase (SMOX) as a cause of DNA damage, and the importance of phosphorylation of EGFR and ERBB2 as a molecular signature of gastric carcinogenesis. In this P01, in addition to the long-term follow-up of the high risk Colombian cohort, we will include new study populations in Central America, where NCI-funded infrastructures are in place, as this region represents the core low/middle income countries (LMICs) of Latin America with linkage to significant U.S. Hispanic immigrant populations. The overarching objective of this P01 renewal application is to develop new understanding of gastric carcinogenesis through studies incorporating analyses of human and H. pylori genetics, and gene methylation (Project 1), the interaction of H. pylori with parasitic infection and the gastric microbiota (Project 2), and molecular mechanisms of gastric carcinogenesis focused on novel pathways for oxidative DNA damage (Project 3). These projects each explore distinct hypothesis, but are tightly integrated in their focus on developing novel strategies for risk stratification and prevention of gastric cancer. The individua projects are: Project 1, Epidemiologic studies of gastric carcinogenesis (PI - Douglas M. Morgan); Project 2, The influence of gastric microbiota, intestinal helminths and host immune responses in cancer risk (PI - James G. Fox); Project 3, Molecular signatures of gastric carcinogenesis in the host response to H. pylori (PI - Keith T. Wilson). These studies are enriched by three cores: Histopathology (Core A); Administrative (Core B); and Fieldwork (Core C). The unique and highly developed expertise brought to this P01 includes global health and epidemiology, human and bacterial genetics, microbiology, immunology, cancer biology, pathology, and gastroenterology. Collectively, these cross-disciplinary studies are extremely well-positioned to bring to fruition bold and exciting new concepts in gastric cancer molecular epidemiology, with direct translational relevance to specific risk assessment and prevention strategies.

描述(申请人提供)：胃腺癌是主要的感染相关癌症，是全球癌症死亡的第三大常见原因。幽门螺杆菌感染了世界上一半以上的人口和高达85%的发展中国家居民，但缺乏预防方案和生物标记物来识别高危菌株和管理癌症前病变患者。该计划项目赠款通过利用拉丁美洲广泛和组织良好的基础设施，为胃癌研究做出了开创性的贡献，这些基础设施围绕着哥伦比亚高癌症风险安第斯地区以前的一项化学预防试验的独特的长期人类受试者队列组织。主要成就包括与以下方面有关的发现：1)高风险(山区)与低风险(沿海)癌症风险地区；2)幽门螺杆菌菌株的系统地理起源以及人类宿主与感染株之间的遗传错配与疾病的进展直接相关；3)重要的疾病修饰因素，包括胃微生物区系与并发寄生虫感染；4)多胺的因果作用，特别是精胺被精胺氧化酶(SMOX)氧化导致DNA损伤，以及EGFR和ERBB2磷酸化是胃癌发生的重要分子标志。在P01中，除了对哥伦比亚高危人群进行长期跟踪外，我们还将纳入中美洲的新研究人群，那里有NCI资助的基础设施，因为该地区代表着拉丁美洲的核心低/中等收入国家(LMIC)，与重要的美国拉美裔移民人口有联系。P01更新申请的主要目标是通过研究人类和幽门螺杆菌的遗传学以及基因甲基化(项目1)、幽门螺杆菌与寄生虫感染和胃微生物区系的相互作用(项目2)以及关注氧化DNA损伤的新途径(项目3)来发展对胃癌发生的新的理解。这些项目每个都探索不同的假设，但都紧密结合在一起，专注于开发新的胃癌风险分层和预防策略。个体项目是：项目1，胃癌发生的流行病学研究(Pi-Douglas M.Morgan)；项目2，胃微生物区系、肠道蠕虫和宿主免疫反应对癌症风险的影响(Pi-James G.Fox)；项目3，幽门螺杆菌宿主反应中的胃癌发生的分子特征(Pi-Keith T.Wilson)。这些研究有三个核心内容：组织病理学(核心A)、行政(核心B)和实地工作(核心C)。P01带来的独特和高度发达的专业知识包括全球健康和流行病学、人类和细菌遗传学、微生物学、免疫学、癌症生物学、病理学和胃肠病学。总体而言，这些跨学科研究处于非常有利的地位，可以实现胃癌分子流行病学中大胆和令人兴奋的新概念，并与具体的风险评估和预防策略直接翻译相关。