B Cell Mechanisms of Tolerance Following Infant Peanut Consumption

项目摘要/摘要 这份提案详细说明了一项五年计划，为候选人阿多拉·林博士提供知识和专业知识 成为过敏和免疫学领域的独立研究员。拟议的研究是一项 B细胞在婴儿花生过敏与耐受性形成中作用的新研究 被认为是花生过敏的高危人群。尽管研究表明，早期种植花生对高危人群 婴儿可能会影响花生过敏与耐受性的发展，并伴随着 花生特有的免疫球蛋白水平，产生这些免疫球蛋白的B细胞的生物学和 调节这些变化的监管机制尚不清楚。候选人将对B细胞进行评估 婴儿对IL-10、调节性B细胞(B Regs)和B细胞转录组的反应 花生过敏的高风险，在花生引入之前和在花生消费或避免期间都是如此。这个 该项目的具体目标是：1)确定B细胞对IL-10和 B受体频率和功能增加识别对花生过敏的高危婴儿，耐受花生，2) 评价经常食用花生是否增加B细胞对IL-10和B reg的反应性 花生过敏高危婴儿的频率和功能，以及3)确定B细胞转录 与花生耐受性有关的签名。这项研究的发现将解决我们在 关于B细胞在形成食物过敏的关键早期阶段的影响的知识 宽容。这些发现可能会被用于未来评估新生物标记物的研究，以区分 食物过敏与耐受性，新的诊断方法，改进的过敏原免疫治疗监测，以及B类 针对食物过敏的细胞靶向干预。这项研究还将为B细胞生物学提供新的见解。 和婴儿时期的B细胞转录组。候选人已经组建了一支杰出的NIH团队- 资助导师，他们投入时间、专业知识和资源来促进候选人的研究 和职业目标。博拉德博士是世界著名的翻译免疫学家和过继T细胞方面的专家 治疗。格雷里奥博士是食物过敏发病机制方面的领先专家。弗雷什塔特博士有丰富的专业知识 转录学和系统生物学。候选人将参加旨在为她提供 在高级生物统计学、临床研究设计、下一代测序、生物信息学、 以及各个领域的专业发展。她将受益于理想的科学、教育和 由她的初级机构，国家儿童医学中心提供的临床环境，由 乔治华盛顿大学和美国国立卫生研究院的培训机会。总而言之，这是 建议书描述了相关和可行的研究项目和职业发展计划，该计划将使 候选人，以获得独立的NIH资金，并在学术食物过敏的利基领域确立自己的地位。

PROJECT SUMMARY/ABSTRACT This proposal details a 5-year plan to provide the candidate, Dr. Adora Lin, with the knowledge and expertise to become an independent investigator in the field of Allergy and Immunology. The proposed research is a novel investigation of the role of B cells in the development of peanut allergy versus tolerance in infants deemed at high risk for peanut allergy. Although studies suggest that early introduction of peanut to high-risk infants can influence the development of peanut allergy versus tolerance, with accompanying changes in peanut-specific immunoglobulin levels, the biology of the B cells producing these immunoglobulins and regulatory mechanisms mediating these changes are unknown. The candidate will evaluate the B cell response to IL-10, regulatory B cells (B regs), and the B cell transcriptome in samples collected from infants at high risk for peanut allergy, both prior to peanut introduction and during peanut consumption or avoidance. The specific aims of the project are: 1) To determine whether increased B cell responsiveness to IL-10 and increased B reg frequency and function identify infants at high risk for peanut allergy who tolerate peanut, 2) To evaluate whether regular peanut consumption augments B cell responsiveness to IL-10 and B reg frequency and function in infants at high risk for peanut allergy, and 3) To define the B cell transcription signature associated with peanut tolerance. Findings from this research will address significant gaps in our knowledge regarding the impact of B cells during the critical early period that shapes food allergy versus tolerance. These findings may be leveraged into future studies evaluating novel biomarkers for distinguishing food allergy versus tolerance, new diagnostic methods, improved monitoring of allergen immunotherapy, and B cell-targeted interventions for food allergy. This research will also provide new insights into B cell biology, B regs, and the B cell transcriptome during infancy. The candidate has assembled an outstanding team of NIH- funded mentors, who have committed their time, expertise, and resources to facilitate the candidate's research and career goals. Dr. Bollard is a world-renowned translational immunologist and expert in adoptive T cell therapies. Dr. Guerrerio is a leading expert in food allergy pathogenesis. Dr. Freishtat has extensive expertise in transcriptomics and systems biology. The candidate will participate in coursework designed to provide her with further skills in advanced biostatistics, clinical study design, next-generation sequencing, bioinformatics, and various areas of professional development. She will benefit from an ideal scientific, educational, and clinical environment provided by her primary institution, Children's National Medical Center, enhanced by training opportunities at the George Washington University and National Institutes of Health. In summary, this proposal describes a relevant and feasible research project and career development plan that will position the candidate to secure independent NIH funding and establish herself in a niche area of academic food allergy.