Crosstalk between MAIT cells and the microbiota

MAIT 细胞和微生物群之间的串扰

• 批准号: 10404907
• 负责人: Michael George Constantinides
• 金额: $ 10.8万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404907
• 关键词: 16S ribosomal RNA sequencing; Address; Animals; Antigen-Presenting Cells; Award; Bacteria; Basic Science; Bioinformatics; Breathing; Cells; Clinical Research; Communication; Core Facility; Cutaneous; Data; Data Set; Dermatitis Herpetiformis; Development; Disease; Educational process of instructing; Educational workshop; Enrollment; Enterobacteria phage P1 Cre recombinase; Environment; Epithelial Cells; Faculty; Feces; Frequencies; Germ-Free; Gnotobiotic; Goals; Health; Homeostasis; Human; Immune; Immune response; Immunity; Individual; Infectious Skin Diseases; Inflammatory; Institution; Interleukin-1; Interleukin-17; Intestines; Intramural Research Program; K22 Award; Laboratories; Lactobacillus; Lymphocyte; Manuscripts; Mentors; Microbe; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Peripheral; Population; Postdoctoral Fellow; Production; Psoriasis; Research; Research Personnel; Resources; Riboflavin; Seeds; Series; Signal Transduction; Skin; Source; Staphylococcus epidermidis; Swab; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Tamoxifen; Time; Tissues; Training; Translating; Translational Research; United States National Institutes of Health; Work; animal facility; antimicrobial peptide; base; career; career development; clinical application; conditional knockout; cytokine; experimental study; fungus; germ free condition; gut colonization; gut microbiota; immune system function; improved; insight; interleukin-22; interleukin-23; keratinocyte; meetings; microbial; microbial colonization; microbial community; microbiome; microbiota; mouse model; novel; pathogen; programs; response; skills; skin disorder; subcutaneous; symposium; teacher mentor; transcriptome sequencing

Project Summary/Abstract Career Goals: My overarching career goal is to become an independent investigator at an academic institution where I study how the microbiota impacts the development and function of the immune system, ultimately translating my findings into novel treatments. I also aspire to become an inspirational teacher and mentor. Career Development: In addition to meeting weekly with Dr. Belkaid, I will discuss my progress with my mentors at least once every 6 months for the duration of the award. The NIH has numerous training resources which will be pivotal to my development, including courses and workshops. I will enhance my ability to analyze computational datasets by participating in bioinformatics courses, enroll in courses to improve my teaching and mentoring, and attend seminars on the transition to independence and management. I will further develop my communication skills prior to the K22 award by authoring 2 manuscripts and presenting at least 8 times at seminars and conferences. Environment: The NIH Intramural Research Program has more than 1,200 PIs conducting basic, translational, and clinical research, a plethora of core facilities, and resources for the career development of postdocs. The NIAID Microbiome Program has a gnotobiotic animal facility and a sequencing facility that also provides bioinformatics analysis. There are numerous seminar series featuring external faculty and others that allow trainees to present their research. Prior to the K22 award, I will work in the laboratory of Dr. Belkaid, which is a BSL-2 research space and is adequately equipped to conduct the proposed experiments. Research: Skin infections are the 4th most prevalent cause of disease globally, indicating that cutaneous diseases are a major health concern. In addition to inhibiting colonization by pathogens through competition and the induction of immune responses, the microbiota promotes immune homeostasis via the release of microbial products. Human skin harbors mucosal-associated invariant T (MAIT) cells, which rapidly produce either Th1- or Th17-associated cytokines in response to microbial vitamin B2 derivatives presented by the MHC-Ib molecule, MR1. We have recently found that IL-17A+ MAIT cells are highly abundant in murine skin and depend on the microbiota. However, the mechanism by which commensals promote MAIT cell development remains unknown. To address this, I will identify microbes that induce MAIT cell development and elucidate the mechanism using an Mr1f/f conditional knockout and other murine models. Administration of these commensals to mice challenged with cutaneous pathogens will establish whether the microbiota can enhance the contribution of MAIT cells to skin immunity, which could have clinical applications due to the high frequency of cutaneous MAIT cells.

项目总结/摘要 职业目标：我的首要职业目标是成为一个学术机构的独立调查员 在那里我研究微生物群如何影响免疫系统的发育和功能， 将我的发现转化为新的治疗方法我也渴望成为一名鼓舞人心的教师和导师。 职业发展：除了每周与Belkaid博士会面外，我还会与我的导师讨论我的进步 最少每6个月一次，在奖励期内。国家卫生研究院有大量的培训资源， 对我的发展至关重要，包括课程和研讨会。我会提高我的分析能力 通过参加生物信息学课程来计算数据集，报名参加课程以提高我的教学水平， 辅导，并参加关于向独立过渡和管理的研讨会。我将进一步发展我的 在K22奖之前，通过撰写2篇手稿并至少8次在 研讨会和会议。 环境：美国国立卫生研究院校内研究计划有1,200多个PI进行基础，翻译， 和临床研究，过多的核心设施，以及博士后职业发展的资源。的 NIAID微生物组计划有一个gnotobiotic动物设施和测序设施，也提供 生物信息学分析有许多研讨会系列具有外部教师和其他人，允许 学员介绍他们的研究。在获得K22奖之前，我将在贝尔凯德博士的实验室工作， BSL-2研究空间，并有足够的设备进行拟议的实验。 研究：皮肤感染是全球第四大最常见的疾病原因，这表明皮肤感染 疾病是一个主要的健康问题。除了通过竞争抑制病原体的定殖外， 在诱导免疫应答时，微生物群通过释放微生物来促进免疫稳态， 产品.人类皮肤含有粘膜相关的不变T（MAIT）细胞，其快速产生Th 1- 或Th 17相关细胞因子对由MHC-Ib分子呈递的微生物维生素B2衍生物的应答， MR 1。我们最近发现IL-17 A + MAIT细胞在小鼠皮肤中高度丰富，并且依赖于皮肤中的细胞因子。 微生物群然而，β-唾液酸促进MAIT细胞发育的机制仍不清楚。 为了解决这个问题，我将鉴定诱导MAIT细胞发育的微生物，并使用 Mr 1f/f条件性敲除和其它鼠模型。对激发的小鼠给予这些药物 将确定微生物群是否可以增强MAIT细胞对皮肤病原体的贡献， 皮肤免疫，由于皮肤MAIT细胞的高频率，其可能具有临床应用。