Self and dietary lipid antigens for invariant natural killer T cells

描述（由申请人提供）：该提案详细说明了一个五年培训计划，用于开发一个专注于不变自然杀伤T （iNKT）细胞生物学和这些细胞的脂质抗原的研究项目。iNKT细胞是先天样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，iNKT细胞识别脂质抗原。iNKT细胞识别的脂质抗原尚未被很好地理解，并且是免疫学界的重要兴趣。该候选物最近通过鉴定β -葡萄糖神经酰胺（β - glcer）作为iNKT细胞的有效自身抗原，在该领域取得了重大进展。有趣的是，除了作为一种自身抗原，β - glccer也存在于人类饮食中，候选人已经确定了激活iNKT细胞的β - glccer的饮食形式。在哺乳动物和人类饮食中都存在许多β - glcer的结构变异。对于自身和膳食脂质来源，个体β - glccer变体激活iNKT细胞的能力取决于它们的鳍结构细节。本研究的目标是：1)研究β - glccer作为iNKT细胞脂质抗原活性的结构要求；2)确定β - glccer水平和结构在疾病中是如何调节的；3)通过评估β - glccer作为膳食脂质抗原对微生物防御的后续影响来确定其功能作用。由于iNKT细胞在多种疾病过程中发挥重要作用，因此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在脂质化学，实验设计，科学交流和疾病的免疫机制方面获得进一步的经验。具体的职业发展计划由导师和候选人共同描述。导师迈克尔·布伦纳博士在研究领域非常有名望，并且有很强的培训记录。候选人的长期职业目标是获得终身教职

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.