NKT cell mediated immunoregulation by symbiotic gut microbial glycosphingolipids

共生肠道微生物鞘糖脂介导的 NKT 细胞免疫调节

• 批准号: 9034354
• 负责人: Sungwhan F Oh
• 金额: $ 10.94万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2020-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034354
• 关键词: Address; Advisory Committees; Agonist; Anabolism; Analytical Chemistry; Animals; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; Bacteria; Bacteroides fragilis; Binding; Biological; Birth; Cell Count; Colitis; Development; Disease; Environment; Enzymes; Germ-Free; Glycolipids; Glycosphingolipids; Goals; Gut associated lymphoid tissue; Homeostasis; Human; Immune; Immune system; Immunity; Immunologics; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Knock-out; Knowledge; Large Intestine; Ligands; Lipids; Lower Gastrointestinal Tract; Maps; Mediating; Mediator of activation protein; Mentors; Mentorship; Microbiology; Molecular; Molecular Structure; Mus; Natural Immunity; Pathway interactions; Pharmaceutical Preparations; Play; Population; Principal Investigator; Process; Reaction; Regulation; Reporting; Research; Role; Shapes; Signal Transduction; Site; Sphingolipids; Stimulus; Structure; Syndrome; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte Subsets; Training; Wild Type Mouse; Work; adaptive immunity; analytical method; base; commensal microbes; design; experience; genome-wide; gut microbiota; immunoregulation; in vivo; interest; killer T cell; lipid mediator; metabolomics; microbial; microbial colonization; mutant; novel; public health relevance; receptor; response; screening; small molecule; tandem mass spectrometry

 DESCRIPTION (provided by applicant): Mammalian hosts and their intestinal microbiota have co-evolved over millennia. Although customarily described as "commensal," the microbiota of the gut is now known to be crucial for the normal development of host immunity and for the homeostasis of the immune system. An imbalance in microbial colonization-dysbiosis-is associated with diverse inflammatory and autoimmune syndromes, such as the inflammatory bowel diseases of the lower gastrointestinal tract. During normal immunologic development and pathophysiological reactions to challenges, small molecules produced by commensal microbes, such as lipids, can play crucial roles in shaping the immune system and its responses. Bacteroides fragilis, a well-studied resident of the human lower gastrointestinal tract, exerts interesting immune-modulating biological effects in various autoimmune diseases. In germ-free mice, wild-type B. fragilis monocolonization suppresses gut natural killer T cell (NKT cell) numbers and protects the animals from NKT cell-mediated colitis, whereas a sphingolipid- knockout strain does not provide such protection. Primary results imply that unique sphingolipid mediators originated from B. fragilis can contribute to these protective mechanisms. The current proposal describes a 5-year plan of mentored research focusing on the unique sphingolipids produced by B. fragilis and other commensal Bacteroidales and assessing their ability to modulate host immunity and protect the host from excessive inflammation. This work addresses three specific aims: (1) Acquire a comprehensive sphingolipidomic map of commensal Bacteroidales and investigate biosynthesis pathways of immunoregulatory sphingolipids, (2) Chemically synthesize commensal glycosphingolipids and assess regulation of NKT cell activity and proliferation and (3) Investigate the NKT-regulatory functions of commensal glycosphingolipids during immune maturation and upon pathological challenge. In order to attaining these goals, the principal investigator will gain knowledge and experience in microbiology and immunology based on a broad understanding of analytical chemistry and lipid mediator immunology. Didactic and technical training, in conjunction with expert mentorship by Dr. Dennis Kasper (primary mentor) and a scientific advisory committee, will aid in the successful completion of the project, which represents a key step toward independence of the applicant.

 描述（由申请人提供）：哺乳动物宿主及其肠道微生物群已经共同进化了数千年。虽然习惯上被描述为“肠道”，但现在已知肠道的微生物群对于宿主免疫的正常发育和免疫系统的稳态至关重要。微生物定植的不平衡-生态失调-与多种炎症和自身免疫综合征相关，例如下胃肠道的炎症性肠病。在正常的免疫发育和对挑战的病理生理反应中，由微生物产生的小分子，如脂质，可以在塑造免疫系统及其反应中发挥关键作用。 脆弱拟杆菌是一种广泛存在于人类下胃肠道的细菌，在多种自身免疫性疾病中发挥着重要的免疫调节作用。在无菌小鼠中，野生型B. fragilis单菌落定殖抑制肠道自然杀伤T细胞（NKT细胞）数量并保护动物免受NKT细胞介导的结肠炎，而鞘脂敲除菌株不提供这种保护。初步结果表明，独特的鞘脂介质起源于B。fragilis可以促进这些保护机制。 目前的提案描述了一项为期5年的指导研究计划，重点是B产生的独特鞘脂。fragilis和其它类杆菌目的细菌，并评估它们调节宿主免疫和保护宿主免受过度炎症的能力。本研究的目的有三：（1）获得类杆菌目的鞘脂图谱，并研究免疫调节鞘脂的生物合成途径;（2）化学合成类杆菌鞘糖脂，并评估NKT细胞活性和增殖的调节;（3）研究类杆菌鞘糖脂在免疫成熟过程中和病理挑战时的NKT调节功能。为了实现这些目标，主要研究者将在广泛了解分析化学和脂质介体免疫学的基础上获得微生物学和免疫学方面的知识和经验。教学和技术培训，与Dennis Kasper博士（主要导师）和科学咨询委员会的专家指导相结合，将有助于成功完成该项目，这是申请人走向独立的关键一步。