TOX, a Novel Regulator of Thymocyte Selection

TOX，胸腺细胞选择的新型调节剂

基本信息

批准号：
7319650
负责人：
JONATHAN G KAYE
金额：
$ 39.66万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319650
关键词：
Address B-Cell Development Biochemical Biological Process Bone Marrow C-terminal CD8B1 gene Calcineurin Cell Differentiation process Cell Line Cell Lineage Cell Nucleus Cells Characteristics Chimera organism Chromatin Complex DNA Binding Data Decompression Sickness Development Epitopes Event Family member Follow-Up Studies Gene Expression Gene Targeting Genes HMG Domain HMG-Box HMGB Proteins HMGB2 Protein In Situ In Vitro Knock-out Learning Localized Lymphocyte Mammalian Cell Molecular Mus Names Nature Nuclear Nuclear Protein Nuclear Proteins Numbers Pattern Post-Translational Protein Processing Process Proteins RNA Interference Research Personnel Role Signal Pathway Signal Transduction Staging Structure T-Cell Development T-Lymphocyte Thymocyte Selection Thymus Gland Transactivation Transgenic Mice Yeasts chromatin immunoprecipitation domain mapping human prostaglandin D2 receptor in vivo intracellular protein transport member mutant novel progenitor programs protein localization location research study thymocyte yeast two hybrid system

Address B-Cell Development Biochemical Biological Process Bone Marrow C-terminal CD8B1 gene Calcineurin Cell Differentiation process Cell Line Cell Lineage Cell Nucleus Cells Characteristics Chimera organism Chromatin Complex DNA Binding Data Decompression Sickness Development Epitopes Event Family member Follow-Up Studies Gene Expression Gene Targeting Genes HMG Domain HMG-Box HMGB Proteins HMGB2 Protein In Situ In Vitro Knock-out Learning Localized Lymphocyte Mammalian Cell Molecular Mus Names Nature Nuclear Nuclear Protein Nuclear Proteins Numbers Pattern Post-Translational Protein Processing Process Proteins RNA Interference Research Personnel Role Signal Pathway Signal Transduction Staging Structure T-Cell Development T-Lymphocyte Thymocyte Selection Thymus Gland Transactivation Transgenic Mice Yeasts chromatin immunoprecipitation domain mapping human prostaglandin D2 receptor in vivo intracellular protein transport member mutant novel progenitor programs protein localization location research study thymocyte yeast two hybrid system

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项目摘要

DESCRIPTION (provided by applicant): The thymus generates a vast excess of cells that fail to complete maturation and die in situ. This is a result of the processes of beta-selection, positive selection, and negative selection that place stringent controls on various stages of T cell development. Both beta-selection and positive selection are cell differentiation events that result in stable changes in gene expression. There is still much to learn about the molecular control of gene expression during these critical developmental transitions. We have recently identified a gene encoding a novel regulator of thymocyte selection we termed TOX (thymocyte selection associated HMG-box protein). As its name implies, TOX is a member of the HMG-box superfamily of nuclear proteins. HMG-box proteins are architectural factors that bind DNA and regulate formation of mutiprotein transcriptional regulatory complexes and/or are involved in regulating chromatin accessibility. TOX also belongs to a small conserved subfamily of HMG-box proteins. Expression of TOX in the thymus is tightly regulated and is associated with both beta-selection and positive selection. Data indicate that expression of TOX in the thymus of transgenic mice is sufficient to initiate both of these differentiation processes. This includes promotion of CD8 T cell lineage commitment at the expense of CD4 lineage commitment. We propose to further investigate the biological functions of this novel nuclear protein. Specific approaches are outlined to; determine the expression of TOX and family members during lymphocyte development, analyze biochemical characteristics of TOX, determine subcellular and intranuclear localization of the protein, identify signaling pathways that regulate its expression, perform a structure/function analysis of various forms of TOX in vitro and in vivo, produce TOX deficient mice, identify other proteins that interact with domains of TOX and identify gene targets for this nuclear protein in the context of positive selection.

描述（由申请人提供）：胸腺产生大量未能完全成熟并原位死亡的细胞。这是β选择，阳性选择和负面选择过程的结果，这些过程将严格控制在T细胞发育的各个阶段。 β选择和阳性选择都是细胞分化事件，导致基因表达稳定变化。在这些关键发育过渡期间，关于基因表达的分子控制仍然有很多要学习的知识。我们最近确定了一个编码我们称为TOX（胸腺细胞选择相关的HMG-box蛋白）的新型胸腺细胞选择调节剂的基因。顾名思义，TOX是核蛋白质蛋白HMG-box超家族的成员。 HMG-box蛋白是结合DNA并调节烟蛋白转录调节复合物和/或参与调节染色质访问性的结构因子。 TOX还属于HMG-box蛋白的一小部分。托克斯在胸腺中的表达受到严格的调节，并与β选择和阳性选择有关。数据表明，托克斯在转基因小鼠的胸腺中的表达足以启动这两个分化过程。这包括以CD4谱系承诺为代价促进CD8 T细胞谱系承诺。我们建议进一步研究这种新型核蛋白的生物学功能。概述了特定的方法； determine the expression of TOX and family members during lymphocyte development, analyze biochemical characteristics of TOX, determine subcellular and intranuclear localization of the protein, identify signaling pathways that regulate its expression, perform a structure/function analysis of various forms of TOX in vitro and in vivo, produce TOX deficient mice, identify other proteins that interact with domains of TOX and identify gene targets for this nuclear protein in the context of positive选择。