Exploring the function of a novel, microbiota-regulated gene in T cells

探索 T 细胞中新型微生物调节基因的功能

• 批准号: 8621566
• 负责人: June Louise Round
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621566
• 关键词: Animals; Antigens; Apoptosis; Area; Autoimmune Diseases; Autoimmunity; Bacteria; Birth; CD4 Positive T Lymphocytes; Cell Line; Cell Lineage; Cell physiology; Cells; Cellular biology; Data; Defect; Development; Disease; Disease susceptibility; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Exploratory/Developmental Grant; Funding; Gastrointestinal tract structure; Genes; Glean; Grant; Health; Helper-Inducer T-Lymphocyte; Hemoglobin; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; In Vitro; Infection; Inflammatory; Intestines; Knowledge; Lead; Leukemic Cell; Life; Mediating; Metabolism; Molecular; Multiple Sclerosis; Mus; Organism; Pathway interactions; Play; Population; Regulatory T-Lymphocyte; Research; Role; Series; Shapes; Site; Spleen; Sterility; Structure; T-Lymphocyte; Technology; Testing; cell type; commensal microbes; comparative; cytokine; in vivo; microbial; microbial community; mouse model; new therapeutic target; novel; prevent; public health relevance; research study; response; therapeutic target; tool

DESCRIPTION (provided by applicant): The study of commensal-host interactions is a rapidly growing field. Recent advances have uncovered roles for commensal bacteria in shaping the host immune system, metabolism, and pre-disposition or protection from autoimmunity. Thus, the microbiota has emerged as novel mechanism to manipulate human health. Despite the plethora of knowledge that has been gleaned over the last several years, there is gap in our understanding of the molecular mechanisms by which the microbiota can influence these diverse host pathways. T lymphocytes are one of the key cell types that govern adaptive immune responses that lead to antigen specific immunity and immunological memory. In both the intestine and systemic body sites, the microbiota governs the development of multiple T cell subtypes including inflammatory and regulatory T cells. While much research has gone into understanding intestinal T cell biology, little focus has been placed on how the microbiota can influence systemic T cell function. Given that commensal organisms have been presence since the birth of eukaryotic life, it is likely that a sophisticated molecular machinery has evolved witin the host to balance the relationship with the microbiota and the immune system outside of the gut. Much of this machinery will only be realized if we analyze how the immune system develops in the absence of the microbiota. Animals that are born and reared in a completely sterile environment (germfree mice) are a powerful, comparative tool to begin the discovery of novel pathways within the host that govern commensal interactions. Using this approach, we have uncovered a novel gene within T lymphocytes that is dynamically regulated by the microbiota. This gene, ERDR1, has gone un- noticed to this point despite its very high level of expression with key immune cells. We present preliminary data within this proposal that demonstrates that ERDR1 is an important functionally relevant gene in T cell biology and host health. This grant proposes to better understand the mechanisms by which ERDR1 influences host health and microbial community structure.

描述（由申请人提供）：宿主-宿主相互作用的研究是一个快速发展的领域。最近的进展已经揭示了肠道细菌在塑造宿主免疫系统，代谢和易感性或保护自身免疫中的作用。因此，微生物群已经成为操纵人类健康的新机制。尽管在过去几年中已经收集了大量的知识，但我们对微生物群可以影响这些不同宿主途径的分子机制的理解存在差距。T淋巴细胞是控制适应性免疫反应的关键细胞类型之一，适应性免疫反应导致抗原特异性免疫和免疫记忆。在肠道和全身部位，微生物群控制多种T细胞亚型的发展，包括炎症和调节性T细胞。虽然许多研究已经深入了解肠道T细胞生物学，但很少关注微生物群如何影响系统性T细胞功能。考虑到肠道生物自真核生物诞生以来就一直存在，很可能宿主体内进化出了一种复杂的分子机制，以平衡肠道外微生物群和免疫系统的关系。只有当我们分析免疫系统在没有微生物群的情况下如何发展时，这种机制才能实现。在完全无菌的环境中出生和饲养的动物（无菌小鼠）是一个强大的比较工具，可以开始发现宿主内控制肠道相互作用的新途径。使用这种方法，我们发现了T淋巴细胞内的一种新基因，该基因受微生物群的动态调节。这个基因，ERDR 1，已经被忽视了这一点，尽管它的非常高的表达水平与关键的免疫细胞。我们提出的初步数据表明，ERDR 1是一个重要的功能相关的基因在T细胞生物学和宿主健康。这项资助旨在更好地了解ERDR 1影响宿主健康和微生物群落结构的机制。