Project 3: Helicobacter pylori and stomach cancer among Native American populations

项目摘要/摘要：项目3 幽门螺杆菌与美洲土著人群中的胃癌 幽门螺杆菌(Hp)是一种常见的胃部病原体，与十二指肠或十二指肠息肉的发生有关。 胃溃疡、胃癌和粘膜相关淋巴组织(MALT)淋巴瘤。虽然总体上 在美国，胃癌的发病率随着时间的推移而下降，存在明显的种族和 胃癌发病率和相关结果之间的社会经济健康差异。这是一种翻译，多- 方法项目旨在更好地了解幽门螺杆菌感染在胃癌发生中的作用 在亚利桑那州北部的印第安人(NA)中，那里的胃癌发病率约为 是亚利桑那州普通人口的三倍，是与癌症相关的主要原因 死亡率。尽管负担很重，但社会、环境和病原体相关的危险因素仍然未知。 对于这些服务不足的人群。虽然不同人群的流行率不同，但HP在纳瓦霍民族中的流行率 可能很高。我们对72个家庭的初步研究发现，108名参与者中有59%的人尿素呼气Hp阳性 UBT检测，74%的家庭至少有一人呈阳性。此外，对惠普及其 在这些社区中，与胃癌的联系很低。然而，53%的Hp+病例确实在当地城市寻求治疗 印度卫生服务设施，表示关切。在这个不同的人群中，Hp感染的危险因素是 没有明确界定，也不是接受诊断和治疗的障碍，排除了适当的初级 和二级预防策略。因此，目标1是一项以社区为基础的研究，以确定相关因素 感染和自我转诊到临床的障碍。因为Hp亚型可能有助于感染的进展 对于癌症和特定基因类型在该人群中的流行情况尚不清楚，目标2将重点放在 经内窥镜检查的纳瓦霍社区成员Hp亚型分布。两国关系 Hp感染与随后的胃癌之间的关系也与宿主免疫反应有关。肠道 化生和痉挛多肽表达化生(SPEM)是预示 胃癌的发生。SPEM在老鼠身上的研究比在人类身上更深入，因为它可以被诱导 在实验中引入了幽门螺杆菌。Sonic Hedgehog(Shh)配体和Sonic Hedgehog(Shh)配体在上皮中的表达 规范的Hedgehog信号的间质激活在胃动态平衡和胃电活动中起重要作用 炎性细胞的招募。我们早期的研究发现，免疫细胞亚群被招募到胃部 感染期间的上皮细胞变成髓系来源的抑制细胞(MDSCs)，这与顶叶一致。 细胞萎缩和SPEM。Schlafens(SLFN)是一类由1型干扰素强烈诱导的分子家族 与免疫细胞静止有关。利用小鼠细胞的全基因组分析，我们鉴定了一种微小RNA 两种感染小鼠化生胃组织和血清中干扰素调节免疫细胞的特征 和人类。因此，在目标3中，将分析胃活检中的miRNA签名，并将其与其 在内窥镜检查时采集的血清中是否存在。

PROJECT SUMMARY/ABSTRACT: PROJECT 3 HELICOBACTER PYLORI AND STOMACH CANCER AMONG NATIVE AMERICAN POPULATIONS Helicobacter pylori (Hp) is a common gastric pathogen that is associated with the development of duodenal or stomach ulcers, stomach cancer, and mucosa associated lymphoid-tissue (MALT) lymphomas. While the overall incidence of gastric cancer has declined over time in the United States (US), there are clear racial and socioeconomic health disparities in gastric cancer rates and associated outcomes. This translational, multi- method project seeks to better understand the role of Hp infection in the development of stomach cancer among Native Americans (NA) of Northern Arizona where stomach cancer incidence rates are approximately three times as high compared to the general Arizona population and it is the leading cause of cancer-related mortality. Despite this high burden, social, environmental, and pathogen-associated risk factors remain unknown for this underserved population. While prevalence varies within populations, Hp prevalence within Navajo Nation is likely high. Our pilot study of 72 households found 59% of 108 participants were Hp positive by urea breath test (UBT) and 74% of households had at least one person positive. Furthermore, prior knowledge of Hp and its link to stomach cancer is low in these communities. However, 53% of Hp+ cases did seek care at the local urban Indian Health Service facility, indicating concern. Risk factors for Hp infection in this distinct population are not clearly defined nor are barriers to receiving diagnosis and treatment, precluding appropriate primary and secondary prevention strategies. Thus Aim 1 is a community-based study to identify factors associated with infection and barriers to self-referral to clinic. Since Hp subtypes may contribute to progression from infection to cancer and the prevalence of specific genotypes are unknown in this population, Aim 2 will focus on the distribution of Hp subtypes in the Navajo community members referred to clinic for endoscopy. The relationship between Hp infection and subsequent stomach cancer is related also to host immune response. Intestinal metaplasia and Spasmolytic Polypeptide-expressing metaplasia (SPEM) are histologic changes that presage gastric cancer development. SPEM is more intensively studied in mice than humans because it can be induced experimentally after introducing Helicobacter. Epithelial expression of the sonic hedgehog (Shh) ligand and mesenchymal activation of canonical Hedgehog signaling play essential roles in gastric homeostasis and recruitment of inflammatory cells. Our earlier studies found a subset of immune cells recruited to the gastric epithelium during infection become myeloid-derived suppressor cells (MDSCs), and this coincides with parietal cell atrophy and SPEM. Schlafens (SLFN) are a family of molecules strongly induced by type 1 interferons that correlate with immune cell quiescence. Using whole genome analysis of mouse cells, we identified a microRNA signature for this IFN-regulated immune cell in both metaplastic gastric tissue and serum of both infected mice and humans. Thus, in Aim 3 a miRNA signature will be analyzed in the gastric biopsies and compared to its presence in serum collected at time of endoscopy.