Self and dietary lipid antigens for invariant natural killer T cells

描述(由申请人提供)：本提案详细说明了一项为期五年的培训计划，该计划旨在开发一项研究计划，重点是不变自然杀伤T细胞(INKT)的生物学和这些细胞的脂质抗原。INKT细胞是先天T细胞的一个亚群，在宿主防御、变态反应性疾病、自身免疫和癌症中发挥重要作用。大多数T细胞识别多肽抗原，而iNKT细胞识别脂类抗原。INKT细胞识别的脂类抗原还不是很清楚，免疫学界对此很感兴趣。这位候选人最近在该领域取得了重大进展，确定了β-葡萄糖基神经酰胺(β-GlcCer)作为iNKT细胞的有效自身抗原。有趣的是，除了作为一种自身抗原，β-GlcCer还存在于人类饮食中，候选人已经确定了激活iNKT细胞的饮食形式。在哺乳动物和人类饮食中都存在许多β-GlcCer的结构变化。对于自身和饮食中的脂类来源，单个β-GlcCer变体激活iNKT细胞的能力取决于它们的鳍结构细节。这项研究的目标是1)研究作为iNKT细胞脂抗原的β-GlcCer活性的结构要求，2)确定β-GlcCer水平和β-GlcCer结构在疾病中是如何调节的，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细胞在不同的疾病过程中发挥着重要作用，这项工作对人类疾病的影响是深远的。除了建议的实验外，候选人的职业发展目标是在脂肪化学、实验设计、科学交流和疾病的免疫学机制方面获得进一步的经验。导师和应聘者都描述了具体的职业发展计划。这位导师迈克尔·布伦纳博士在研究领域有很好的地位，并有很好的培训记录。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、脂类抗原以及饮食对免疫的影响。

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.