The role of type 2 inflammation in the initiation and progression of metaplastic differentiation and neoplastic transformation of gastric epithelia

本申请请求NCI多样性研究补充资金，以激活NCI赠款

This application requests the NCI diversity research supplement funding to active an NCI grant in response to PA-21-071, to support the research training and career development of a graduate student from an underprivileged racial/ethnic and social/economic background. In this diversity supplement proposal, a predoctoral graduate student will lead a specific project that is immediately relevant and critically complementary to and yet clearly distinct from the parent NCI grant. The diversity supplement proposal is tailored for the graduate student’s interest to understand host-pathogen interaction in gastric tumorigenesis prompted by genetic predisposition of autoimmunity. There is evidence that type 2 inflammation, characterized by the pathway initiated by type 2 cytokine IL4 and IL13, plays a critical role in gastric tumorigenesis initiated by either autoimmunity or H. pylori. The objective in this diversity supplement proposal is to investigate potential synergy of H pylori and autoimmune type 2 inflammation in the initiation and progression of gastric tumorigenesis. In the CTLA4KD model, tumorigenesis is initiated by autoimmunity caused by CTLA4 insufficiency, which mimics the effect of CTLA4 polymorphisms or heterozygous mutations in humans. It is driven by host-intrinsic factor as germ-free conditions did not affect the autoimmunity development and initiation of tumorigenesis. Therefore, the CTLA4 model presents a unique tool to study potential synergy of H pylori and host-intrinsic immune dysregulation, in autoimmune gastritis and its progression to pre-malignancy and cancer. Specifically, the graduate student, while undergoes research training and career development mentoring, will learn to use rigorous scientific reasoning and cutting-edge technology to address the follow two questions: 1) How does H. pylori infection affect gastric autoimmunity and onset of pre-malignancy caused by host-intrinsic dysregulation due to CTLA4 insufficiency? 2) How does H. pylori interact with pre-malignant cells and affect their lineage progression? The student will take a well-crafted curriculum designed for PhD training as well as participate in well-orchestrated career skill activities. The student will work with a mentor team to develop an individual career development plan (IDP) and individualized mentoring plan (IMP), to guide the student through the training process to become independent and creative scholar excelling in conducting interdisciplinary research in microbiology, immunology and cancer biology. Through the research and career training, the student is expected to be not only well-equipped to advance their own scientific careers but also well-prepared to face emerging challenges in the world with creative solutions, with well-rounded scientific professionalism to serve the society.