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: 8026000
• 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/8026000
• 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 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; Pattern; 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，谱系决定转录因子是同时激活和抑制决定细胞命运的基因所必需的。目前，尚不清楚这些因素如何在全球范围内机械地实现这种精确控制。在免疫系统中，幼稚 CD4+ T 辅助细胞一开始有可能成为许多表型不同的谱系，关键转录因子使它们具有适合致病性损伤的明确命运。 T-box 转录因子 T-bet 负责 Th1 细胞谱系的分化。先前的研究表明，T-bet 正向调节效应细胞因子和趋化因子受体，它们是 Th1 细胞分化的原型基因。为了激活这些选定的靶基因，T-bet 参与至少三个物理上可分离的活动：1) H3K27 去甲基化、2) H3K4 甲基化和 3) 独立于染色质环境发生的反式激活事件。然而，目前尚不清楚是否所有目标启动子都需要这些可分离的功能活性，或者更确切地说，它们以特定于上下文的方式被选择性地利用。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 负向调节这些基因的能力是否需要相同或不同的活性尚不清楚。我们将在全局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 定义的功能活性中存在缺陷的突变体构建体，并评估它们在 Th1 细胞分化中调节全局 T-bet 依赖性基因表达模式的能力。我们还将创建缺乏特定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 依赖性基因表达谱方面的生物学相关性。我们将利用这些知识来模拟基于调控模式的 T-bet 依赖性靶基因网络。总之，这些研究将使我们能够定义精确调节 Th1 分化所需的机制。 公共卫生相关性：医学研究中一个令人兴奋的新可能性是有选择地针对人类疾病中致病性改变的个体途径进行治疗干预。这将带来最大的治疗效果，同时将无意的有害副作用降到最低。为了实现分子医学的这一目标，我们必须精确定义维持健康状态的关键因素的个体活动所调节的途径。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，当免疫反应发生改变时，已被证明与 1 型糖尿病、溃疡性结肠炎、多发性硬化症、癌症转移和对传染病的易感性增加等疾病有关。