Molecular Characterization of T-bet's Role in Immunity

T-bet 在免疫中的作用的分子表征

• 批准号: 8212463
• 负责人: Amy Susan Weinmann
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212463
• 关键词: Address; Adult; Adverse effects; Autoimmune Process; Biological; Boxing; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Classification; Cleft Palate; Commit; Communicable Diseases; Congenital Heart Defects; Development; Developmental Gene; Disease; Embryonic Development; Environment; Epigenetic Process; Event; Family; Family member; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Hereditary Disease; Histones; Human Genetics; Immune response; Immune system; Immunity; Immunodeficiency and Cancer; Incidence; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Limb structure; Logic; Medical Research; Methylation; Modeling; Molecular; Molecular Medicine; Molecular Profiling; Multiple Sclerosis; Mus; Neoplasm Metastasis; Network-based; Pathway interactions; Pituitary Gland; Play; Predisposition; Proteins; Recruitment Activity; Regulation; Research; Role; Series; System; T-Lymphocyte; Th1 Cells; Therapeutic; Therapeutic Intervention; Tissues; Transactivation; Ulcerative Colitis; Work; chemokine receptor; cytokine; demethylation; gene repression; human disease; in vivo; mouse model; mutant; programs; promoter; public health relevance; transcription factor

DESCRIPTION (provided by applicant): At cell fate decision checkpoints, a precise series of events occur to establish developmentally appropriate gene expression profiles. At the molecular level, lineage-determinant transcription factors are required for the simultaneous activation and repression of genes that define the fate of a cell. Currently, it is unclear how these factors mechanistically achieve this precise control on a global level. In the immune system, naive CD4+ T helper cells begin with the potential to become a number of phenotypically distinct lineages, with key transcription factors committing them to a defined fate that is appropriate for a pathogenic insult. The T-box transcription factor T-bet is responsible for the differentiation of the Th1 cell lineage. Previous work has shown that T-bet positively regulates the effector cytokines and chemokine receptors that are the prototypic genes in Th1 cellular differentiation. To activate these select target genes, T-bet participates in at least three physically separable activities: 1) H3K27-demethylation, 2) H3K4-methylation, and 3) transactivation events that occur independent from the chromatin environment. It is currently unclear, however, whether these separable functional activities are required at all target promoters, or rather they are selectively utilized in a context-specific manner. In addition, the mechanism by which T-bet represses the gene expression profiles for the alternative helper T cell lineages and whether T-bet's ability to negatively regulate these genes requires the same or distinct activities is unknown. We will examine these questions on both a global and select target gene level. To this end, we will utilize mutant constructs deficient in each of T-bet's defined functional activities and assess their ability to regulate the global T-bet-dependent gene expression patterns in Th1 cell differentiation. We also will create mice deficient in defined interacting proteins to determine their biological relevance in regulating T-bet-dependent gene expression profiles in Type 1 immune responses. We will utilize this knowledge to model T-bet-dependent target gene networks that are based upon the mode of regulation. Together, these studies will allow us to define the mechanisms that are needed for the precise regulation of Th1 differentiation. PUBLIC HEALTH RELEVANCE: A new and exciting possibility in medical research is to selectively target therapeutic interventions for individual pathways that are pathogenically altered in human disease. This will allow for the greatest therapeutic benefit with the least number of unintentional detrimental side effects. In order to accomplish this goal in molecular medicine, we must precisely define the pathways that are regulated by the individual activities of the key factors involved in maintaining a healthy state. Our studies will address this from the standpoint of a key factor that regulates immune responses, which when altered, has been shown to be associated with diseases such as type 1 diabetes, ulcerative colitis, multiple sclerosis, cancer metastasis, and increased susceptibility to infectious disease.

描述(由申请人提供)：在细胞命运决定检查点，发生一系列精确的事件，以建立适合发育的基因表达谱。在分子水平上，决定细胞命运的基因的同时激活和抑制需要谱系决定转录因子。目前，尚不清楚这些因素是如何在全球层面上机械地实现这种精确控制的。在免疫系统中，幼稚的CD4+T辅助细胞一开始有可能成为一些表型不同的谱系，关键的转录因子使它们受到特定的命运，这适合于病原性侮辱。T-box转录因子T-bet负责Th1细胞谱系的分化。以前的工作表明，T-bet正向调节Th1细胞分化的原型基因--效应细胞因子和趋化因子受体。为了激活这些选定的靶基因，T-bet至少参与了三个物理上可分离的活动：1)H3K27-去甲基化，2)H3K4-甲基化，以及3)独立于染色质环境发生的反式激活事件。然而，目前尚不清楚这些可分离的功能活动是否对所有目标启动子都是必需的，或者更确切地说，它们是以特定于上下文的方式有选择地利用的。此外，T-bet抑制替代辅助T细胞谱系的基因表达谱的机制，以及T-bet负调控这些基因的能力是否需要相同或不同的活动尚不清楚。我们将在全球和选定的目标基因水平上研究这些问题。为此，我们将利用在每个T-bet定义的功能活动中都存在缺陷的突变结构，并评估它们在Th1细胞分化中调节全球T-bet依赖的基因表达模式的能力。我们还将创建缺乏明确相互作用蛋白的小鼠，以确定它们在调节1型免疫反应中T-bet依赖的基因表达谱方面的生物学相关性。我们将利用这一知识来建模基于调控模式的T-bet依赖的靶基因网络。总之，这些研究将使我们能够定义精确调控Th1分化所需的机制。 公共卫生相关性：医学研究中一种新的、令人兴奋的可能性是有选择地针对人类疾病中发生病理性改变的个别途径进行治疗干预。这将允许以最少的非故意有害副作用获得最大的治疗益处。为了在分子医学中实现这一目标，我们必须准确地定义由维持健康状态所涉及的关键因素的个体活动调节的途径。我们的研究将从调节免疫反应的关键因素的角度来解决这个问题，当免疫反应改变时，已被证明与1型糖尿病、溃疡性结肠炎、多发性硬化症、癌症转移和传染病易感性增加等疾病有关。