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

此申请要求NCI多样性研究补充资金，以积极响应NCI赠款 PA-21-071，以支持研究生的研究培训和职业发展，从一个 贫困的种族/民族和社会/经济背景。在这一多样性补充提案中， 博士前研究生将领导一个具体的项目，是立即相关和关键的补充 但与父母的NCI补助金明显不同。多样性补充提案是为毕业生量身定制的 学生有兴趣了解宿主-病原体相互作用在胃肿瘤发生中， 自身免疫的倾向。有证据表明，2型炎症，其特征在于途径 由2型细胞因子IL 4和IL 13启动的胃肿瘤，在由以下任一种启动的胃肿瘤发生中起关键作用： 自身免疫或H.幽门。本多样性补充提案的目的是调查潜在的协同作用 幽门螺杆菌和自身免疫性2型炎症在胃肿瘤发生的启动和发展。在 在CTLA 4KD模型中，肿瘤发生是由CTLA 4不足引起的自身免疫引发的，其模拟了CTLA 4KD模型。 CTLA 4多态性或杂合突变对人类的影响。它由宿主内在因素驱动， 无菌条件不影响自身免疫的发展和肿瘤发生的起始。因此 CTLA 4模型为研究幽门螺杆菌与宿主内在免疫的潜在协同作用提供了独特的工具 在自身免疫性胃炎及其向癌前病变和癌症的进展中，具体而言是 研究生在接受研究培训和职业发展指导的同时，将学会使用 严谨的科学推理和尖端的技术来解决以下两个问题：1）H。 幽门螺杆菌感染影响胃自身免疫和宿主内源性失调引起癌前病变发生 是因为CTLA 4不足吗2)H怎么样幽门螺杆菌与癌前细胞相互作用并影响其谱系 进展？学生将参加精心设计的博士培训课程，并参加 精心策划的职业技能活动。学生将与导师团队合作，发展个人职业生涯 发展计划（IDP）和个性化辅导计划（IMP），以指导学生完成培训 过程成为独立和创造性的学者擅长进行跨学科研究， 微生物学、免疫学和癌症生物学。通过研究和职业培训，学生有望 不仅要有良好的装备来推进自己的科学事业，而且要做好充分的准备来面对新兴的 以创造性的解决方案应对世界挑战，以全面的科学专业精神服务社会。

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.