Self and dietary lipid antigens for invariant natural killer T cells

恒定自然杀伤 T 细胞的自身和饮食脂质抗原

• 批准号: 8580641
• 负责人: Patrick Joseph Brennan
• 金额: $ 18.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-11 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580641
• 关键词: Activities of Daily Living; Affect; Allergic Disease; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmunity; Binding; Biology; CCL4 gene; Cell surface; Cells; Communication; Communities; Data; Development Plans; Diet; Dietary Fats; Dietary intake; Dimensions; Disease; Experimental Designs; Faculty; Fatty Acids; Food; Galactosylceramides; Gene Silencing; Glucosylceramides; Goals; Histocompatibility; Homeostasis; Host Defense; Human; Human body; Hypersensitivity; Immune response; Immune system; Immunity; Immunologics; Immunology; In Vitro; Individual; Infection; Inflammatory; Lead; Lipid Chemistry; Lipids; Lung; Malignant Neoplasms; Mammals; Mentors; Modeling; Molecular; Mus; Names; Nature; Pathway interactions; Pattern; Peptides; Phase; Play; Pneumococcal Infections; Population Dynamics; Positioning Attribute; Process; Research; Role; Signal Transduction; Source; Soy Milk; Sterility; Stimulus; Streptococcus pneumoniae; Structure; Surface; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Training; Variant; Work; base; career; career development; cytokine; experience; feeding; field study; fighting; human disease; in vivo; interest; killer T cell; microbial; programs; public health relevance; research study

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.

描述（由申请人提供）：该提案详细介绍了针对这些细胞不变的天然杀伤（Inkt）细胞和脂质抗原的生物学制定的五年培训计划。 Inkt细胞是先天性T细胞的子集，在宿主防御，过敏性疾病，自身免疫性和癌症中起重要作用。虽然大多数T细胞识别肽抗原，但Inkt细胞识别脂质抗原。 inkt细胞识别的脂质抗原尚不清楚，并且对免疫学群落具有重大关注。该候选人最近通过将β-葡萄糖基酰胺（β-GLCCER）作为inkt细胞的有效自抗原来向前迈出了重要的一步。有趣的是，除了成为自抗原外，在人类饮食中还发现了β-葡萄球菌，候选人还确定了激活Inkt细胞的饮食形式。在哺乳动物和人类饮食中都存在β-glccer的许多结构变化。对于自我和饮食脂质的来源，单个β-GLCCER变体激活Inkt细胞的能力取决于其FIN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β-GLCCER水平和β-GLCCER结构如何在疾病中调节β-GLCCER结构，以及3）确定β-GLCCER的功能作用，通过评估脂肪抗原对脂肪抗原的效果，对其进行脂肪抗原的效果，以对其进行微生物效应。由于Inkt细胞在各种疾病过程中起着重要作用，因此这项工作对人类疾病的影响是深远的。除了提出的实验外，候选人的职业发展目标是获得脂质化学，实验设计，科学交流和疾病免疫学机制的进一步经验。导师和候选人都描述了一项特定的职业发展计划。这位导师迈克尔·布伦纳（Michael Brenner）博士在研究领域已经建立了很好的建立，并且具有很强的培训记录。候选人的长期职业目标是获得终身任职的职位 并继续他对Inkt细胞，脂质抗原以及饮食对免疫的影响的研究。