H. Pylori Relationship to Digestive Diseases and Cancer

总结 本申请是根据特别关注通知（NOSI）NOT-CA-23-038提交的， 一个目标，以支持指导癌症研究的职业发展博士紫罗兰Kayamba，一个早期低， 来自赞比亚的中等收入国家（LMIC）调查员（ESLI）。这是对我们正在进行的资助的补充， 研究集中在幽门螺杆菌（H. pylori）发病机制和癌症（R 01 CA 077955，PI：Dr Richard Peek），并将由范德比尔特大学医学中心的一个指导小组指导。总体目标 拟议的研究的一个目的是加强Kayamba博士进行世界一流的、高影响力研究的能力 同时定义H的分子机制。幽门相关胃癌发生 胃癌（GC）是赞比亚癌症死亡的主要原因之一，但在赞比亚相对被忽视， 作为一个研究重点。H.幽门螺杆菌感染是胃癌最重要的危险因素， 病原体利用多种策略来操纵宿主免疫反应，确保持久性， 最终引发癌症。在这篇增刊中，我们将调查正在研究的相同分子 在父母补助金，但使用的样本从一个新的撒哈拉以南非洲人口。拟议研究 与母研究的主题一致，即定义致病性微生物操纵的分子途径 H.幽门螺杆菌，驱动具有致癌潜力的免疫反应，特别是白细胞介素-9（IL-9）， 核苷酸结合和寡聚化结构域1（NOD 1）信号传导。 我们假设，作为H。幽门诱导的胃病理学从非萎缩性胃炎发展到 在胃癌的不同阶段，NOD 1水平降低，IL-9表达相应增加， 这些变化可以通过根除感染来逆转。因此，在不同的时间点，胃组织的免疫染色 阶段的致癌过程不仅会提供很大的培训和职业发展的高度 有前途的ESLI，而且还加强了家长研究的科学严谨性。在本补充文件中，目标1将 在不同步骤检查石蜡包埋和冷冻胃活检中的IL-9和NOD 1活化水平 沿着沿着科雷亚大道目的2将比较成功治疗前后IL-9和NOD 1的活化水平 螺杆菌根除幽门感染 本补充研究项目中提出的研究活动将由Kayamba博士进行， 她的团队在赞比亚，使用的方法被采用的母研究。我们相信这 指导的研究将使她成为GC领域的独立研究者和领导者 分子流行病学

Summary This application is being submitted in response to the Notice of Special Interest (NOSI) NOT-CA-23-038 with a goal to support mentored cancer research career development for Dr. Violet Kayamba, an early-stage low- and middle-income country (LMIC) investigator (ESLI) from Zambia. It is a supplement to our ongoing funded study focused on Helicobacter pylori (H. pylori) pathogenesis and cancer (R01 CA077955, PI: Dr Richard Peek), and will be guided by a mentoring team at Vanderbilt University Medical Center. The overarching goal of the proposed research is to strengthen Dr Kayamba’s capacity to conduct world-class, high-impact research while defining molecular mechanisms underlying H. pylori-associated gastric carcinogenesis. Gastric cancer (GC) is one of the leading causes of cancer death in Zambia, but it is relatively neglected in terms of being a research priority. H. pylori infection is the single most important risk factor for GC, and this pathogen utilizes multiple strategies to manipulate the host immune response, ensuring persistence and ultimately triggering carcinogenesis. In this supplement, we will investigate the same molecules being studied in the parent grant, but using samples from a novel sub-Saharan African population. The proposed research is consistent with the theme of the parent study, i.e. to define molecular pathways manipulated by pathogenic H. pylori that drive immune responses with carcinogenic potential, particularly Interleukin-9 (IL-9) and Nucleotide-binding and oligomerization domain containing 1 (NOD1) signaling. We hypothesize that as H. pylori-induced gastric pathology progresses from non-atrophic gastritis through various stages to GC, levels of NOD1 decrease with a corresponding increase in IL-9 expression and that these changes can be reversed by eradicating the infection. Thus, immunostaining of gastric tissue at various stages of the carcinogenic process will not only provide great training and career development to a high promising ESLI, but also strengthen the scientific rigor of the parent study. In this supplement, Aim 1 will examine IL-9 and NOD1 activation levels in paraffin-embedded and frozen gastric biopsies at different steps along the Correa pathway. Aim 2 will compare levels of IL-9 and NOD1 activation before and after successful eradication of H. pylori infection. The research activities proposed in this supplement research project will be carried out by Dr. Kayamba and her team in Zambia, using approaches being employed by the parent study. We are confident that this mentored research will prepare her to become an independent investigator and leader in the field of GC molecular epidemiology.