H. Pylori Relationship to Digestive Diseases and Cancer

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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.