Project 3: Helicobacter pylori and Stomach Cancer Among Native American Populations

项目总结/摘要：项目3 美国本土人群幽门螺杆菌与胃癌 幽门螺杆菌（Helicobacter pylori，Hp）是一种常见的胃病原体，与十二指肠溃疡或 胃溃疡、胃癌和粘膜相关淋巴组织（MALT）淋巴瘤。而整体 在美国（US），胃癌的发病率随着时间的推移而下降，有明显的种族和 胃癌发病率和相关结果的社会经济健康差异。这种翻译，多- 方法项目旨在更好地了解Hp感染在胃癌发展中的作用 在北方亚利桑那州的美洲原住民（NA）中，胃癌发病率约为 与亚利桑那州的一般人口相比，它是癌症相关的主要原因。 mortality.尽管负担很高，但社会、环境和病原体相关的风险因素仍然未知 为这一弱势群体提供服务。虽然流行率在人群中不同，但纳瓦霍族的Hp流行率 可能很高。我们对72个家庭进行的初步研究发现，108名参与者中有59%的人尿素呼气Hp阳性 在UBT测试中，74%的家庭至少有一人呈阳性。此外，Hp的先验知识及其 胃癌的发病率在这些社区很低。然而，53%的Hp+病例确实在当地城市寻求治疗， 印度卫生服务机构，表示关注。在这一特殊人群中，Hp感染的危险因素是 没有明确定义，也没有接受诊断和治疗的障碍， 二级预防战略。因此，目标1是一项以社区为基础的研究，以确定相关因素 感染和自我转诊到诊所的障碍。由于Hp亚型可能会导致感染进展 癌症和特定基因型的患病率在这一人群中是未知的，目标2将侧重于 纳瓦霍社区成员中Hp亚型的分布情况。的关系 幽门螺杆菌感染与胃癌发生之间的关系也与宿主的免疫反应有关。肠 化生和痉挛性多肽表达性化生（SPEM）是组织学变化， 胃癌的发展SPEM在小鼠中的研究比人类更深入，因为它可以诱导 实验性地引入了螺杆菌。上皮细胞表达的音刺猬（Shh）配体和 典型Hedgehog信号传导的间充质激活在胃内稳态中起重要作用， 炎症细胞的募集。我们早期的研究发现，一个免疫细胞亚群被招募到胃， 上皮细胞在感染过程中成为髓源性抑制细胞（MDSC），这与壁细胞的增殖一致。 细胞萎缩和SPEM。Schlafens（SLFN）是由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microRNA， 在两种感染小鼠的化生胃组织和血清中这种IFN调节的免疫细胞的标记 还有人类因此，在目标3中，将在胃活检中分析miRNA标签，并将其与胃活检中的miRNA标签进行比较。 存在于内窥镜检查时采集的血清中。

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.