Investigating the function of human regulatory cells in the intestinal mucosa of

研究人类肠粘膜调节细胞的功能

• 批准号: 8619514
• 负责人: Jeremy Allen Goettel
• 金额: $ 5.51万
• 依托单位: BOSTON CHILDREN'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: 2013-02-12 至 2015-02-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619514
• 关键词: Address; Atrophic; Attenuated; Autoimmunity; Autologous; Award; Basic Science; Biochemical Genetics; Biological; Biological Models; Biology; Boston; CD3 Antigens; CD4 Positive T Lymphocytes; Cell physiology; Cells; Data; Defect; Development; Disease; Doctor of Philosophy; Dose; Engraftment; Environment; Epithelial; Experimental Designs; Experimental Models; Fellowship; Fostering; Foundations; Functional disorder; Funding; Gastrointestinal tract structure; Genetic Techniques; Goals; Health; Homeostasis; Homing; Human; Immune; Immune System Diseases; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory disease of the intestine; Injury; Interleukin-10; Interleukin-2; Intestinal Mucosa; Intestines; Lead; Leukocytes; Mediating; Mentored Research Scientist Development Award; Mentors; Microbiology; Modeling; Morbidity - disease rate; Mouse Strains; Mucous Membrane; Mus; National Research Service Awards; Pathogenesis; Pathology; Patients; Pediatric Hospitals; Positioning Attribute; Productivity; Publications; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Signal Transduction; Sulfonic Acids; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Trinitrobenzenes; Ulcer; Ulcerative Colitis; Work; Xenobiotics; base; career; career development; clinically significant; experience; gastrointestinal; human subject; immune activation; in vivo; insight; interdisciplinary collaboration; interest; intestinal villi; medical schools; mouse model; novel; peripheral blood; planetary Atmosphere; programs; public health relevance; reconstitution; research study; transcription factor

DESCRIPTION (provided by applicant): The candidate holds a Ph.D. with an extremely strong commitment to basic science research, and a specific interest in gastrointestinal mucosal immunology. The candidates short-term goals for this fellowship are 1) to become proficient in immunology using biochemical and genetic techniques to investigate mechanistically immune-mediated pathologies; 2) to acquire expertise in conceptually and technologically cutting-edge approaches to experimental design that can elucidate the role of human regulatory T cells in intestinal inflammation; 3) to develop professional experience in fostering creative and highly interdisciplinary collaborations between experts in immunology, epithelial biology and microbiology; 4) to produce sufficient preliminary data and publications that will serve as the basis for a competitive K01 application. The candidate's long-term career goal is to become an independently funded investigator and make meaningful contributions to our knowledge of gastrointestinal mucosal immunology to benefit human health. The overall theme of this project is to understand the mechanisms and requirements by which human regulatory T cells function in the gut mucosa to promote immune homeostasis. Studies implicate Tregs as critical negative regulators of effector T cell responses in both mice and humans. For immune-mediated diseases and immunodeficiencies, Treg dysfunction is associated with disease pathogenesis and morbidity. While experimental data implicate a role for murine Tregs in mucosal homeostasis, insight into the role of human Tregs during intestinal inflammation is not well characterized due to restrictions on experimenting with human subjects and access to relevant tissues. To address this problem, we will utilize a mouse model capable of engrafting human leukocytes to examine the role of Tregs during intestinal inflammation using two experimental T cell-mediated models of intestinal inflammation, anti-CD3-mediated small intestinal enteropathy and TNBS-mediated colonic inflammation. The specific goal of this study is to test the hypotheses: Human Tregs function in a xenobiotic system to suppress human T cell-mediated intestinal inflammation in a TGF-beta and IL-10 dependent manner. The proposed work will be pursued within the context of an intensive and formalized career development program, which will allow the candidate to acquire expertise in both classic and leading edge immunology and cell biological approaches to studying intestinal immune homeostasis. In addition, a diverse group of researchers at Children's Hospital Boston and Harvard Medical School with expertise in immune regulation and mucosal immunology will be established to oversee the candidate's progress. The research environment will provide an intellectually enriching, technically resourceful and collaborative atmosphere that will catalyze the candidate's scientific productivity. At the conclusion of the award period, the candidate will be well positioned as an applicant for an independent K01 award.

描述（由申请人提供）：候选人拥有博士学位。对基础科学研究的强烈承诺以及对胃肠道粘膜免疫学的特定兴趣。候选人的短期目标是1）使用生化和遗传技术来精通免疫学来研究机械免疫介导的病理学； 2）在概念和技术上尖端的实验设计方面获得专业知识，以阐明人类调节性T细胞在肠道炎症中的作用； 3）在促进免疫学，上皮生物学和微生物学专家之间培养创造性和高度跨学科合作方面的专业经验； 4）生产足够的初步数据和出版物，这些数据和出版物将作为竞争性K01应用程序的基础。候选人的长期职业目标是成为一名独立资助的研究者，并为我们对胃肠道粘膜免疫学了解以使人类健康做出有意义的贡献。该项目的总体主题是了解人类调节性T细胞在肠粘膜中起作用以促进免疫稳态的机制和要求。研究暗示Treg是小鼠和人类效应T细胞反应的关键负调节剂。对于免疫介导的疾病和免疫缺陷，TREG功能障碍与疾病发病机理和发病率有关。虽然实验数据暗示了鼠Treg在粘膜稳态中的作用，但由于对人类受试者进行实验和获得相关组织的限制，人们对人tregs在肠道炎症中的作用的见解尚未得到很好的特征。为了解决这个问题，我们将使用一种能够雕刻人类白细胞的小鼠模型来检查Treg在肠道炎症过程中的作用，使用两个实验性T细胞介导的肠炎，抗CD3介导的抗CD3介导的小肠肠病和TNBS介导的结肠炎症。这项研究的具体目的是检验假设：人treg在异种生物系统中起作用，以抑制人类T细胞介导的肠道炎症，以TGF-beta和IL-10依赖性方式抑制。拟议的工作将在密集和正式的职业发展计划的背景下进行，这将使候选人能够在研究肠道免疫稳态方面获得经典和前缘免疫学和细胞生物学方法的专业知识。此外，将建立一群在波士顿儿童医院和哈佛医学院的多样化研究人员，这些研究人员将在免疫调节和粘膜免疫学方面具有专业知识，以监督候选人的进步。研究环境将提供一种智力丰富，技术上足够的和协作的氛围，这将促进候选人的科学生产力。在颁奖期结束时，候选人将成为独立K01奖的申请人。