Self and dietary lipid antigens for invariant natural killer T cells

描述（由申请人提供）：该提案详细介绍了一项为期五年的培训计划，用于开发一项研究计划，重点是不变的自然杀伤T（iNKT）细胞和这些细胞的脂质抗原的生物学。iNKT细胞是先天性T细胞的一个亚群，在宿主防御、过敏性疾病、自身免疫和癌症中发挥重要作用。虽然大多数T细胞识别肽抗原，但iNKT细胞识别脂质抗原。由iNKT细胞识别的脂质抗原尚未被很好地理解，并且对免疫学界具有重要意义。该候选人最近通过鉴定β-葡萄糖神经酰胺（β-GlcCer）作为iNKT细胞的有效自身抗原，在该领域向前迈出了重要一步。有趣的是，除了作为自身抗原外，β-GlcCer还存在于人类饮食中，并且候选人已经确定了激活iNKT细胞的β-GlcCer的饮食形式。β-GlcCer的许多结构变异存在于哺乳动物和人类饮食中。对于自身和膳食脂质来源，单个β-GlcCer变体激活iNKT细胞的能力取决于其鳍结构细节。拟议研究的目标是：1）研究β-GlcCer活性作为iNKT细胞脂质抗原的结构要求，2）确定疾病中β-GlcCer水平和β-GlcCer结构如何调节，3）通过评估其对微生物防御的后续影响来确定β-GlcCer作为膳食脂质抗原的功能作用。由于iNKT细胞在多种疾病过程中发挥重要作用，这项工作对人类疾病的影响是深远的。除了拟议的实验，候选人的职业发展目标是获得脂质化学，实验设计，科学交流和疾病的免疫机制的进一步经验。具体的职业发展计划由导师和候选人共同描述。导师Michael Brenner博士在研究领域非常成熟，并拥有良好的培训记录。候选人的长期职业目标是获得终身教职 并继续研究iNKT细胞、脂质抗原和饮食对免疫力的影响。

DESCRIPTION (provided by applicant): This proposal details a five year training plan for the development of a research program focused on the biology of invariant natural killer T (iNKT) cells and lipid antigens for these cells. iNKT cells are a subset of innate-like T cells that play n important role in host defense, allergic disease, autoimmunity, and cancer. While most T cells recognize peptide antigens, iNKT cells recognize lipid antigens. The lipid antigens recognized by iNKT cells are not well understood, and are of significant interest to the immunology community. The candidate recently provided a major step forward in the field by identifying beta-glucosylceramide (beta-GlcCer) as a potent self antigen for iNKT cells. Interestingly, in addition to being a self antigen, beta-GlcCer is also found in the human diet, and the candidate has identified dietary forms of beta-GlcCer that activate iNKT cells. Many structural variations of beta-GlcCer exist both in mammals and in the human diet. For both self and dietary lipid sources, the ability of individual beta-GlcCer variants to activate iNKT cells depends on their fin structural details. The goals of the proposed research are 1) to investigate the structural requirements for beta-GlcCer activity as an iNKT cell lipid antigen, 2) to determine how beta-GlcCer levels and beta-GlcCer structure are regulated in disease, and 3) to determine the functional role of beta-GlcCer as a dietary lipid antigen by assessing its subsequent effects on microbial defense. Since iNKT cells play an important role in diverse disease processes, the implications of this work to human disease are far-reaching. In addition to the proposed experiments, the candidate's career development goals are to gain further experience with lipid chemistry, experimental design, scientific communication, and the immunologic mechanisms of disease. A specific career development plan is described by both the mentor and candidate. The mentor, Dr. Michael Brenner, is very well established in the field of study, and has a strong training record. The candidate's long-term career goal is to attain a tenure-track faculty position and to continue his research on iNKT cells, lipid antigens, and the effects of diet on immunity.