ORPHAN NUCLEAR RORgammat IN THYMOCYTE DIFFERENTIATION

胸腺细胞分化中的孤儿核 RORgammat

• 批准号: 6651503
• 负责人: You-Wen He
• 金额: $ 30.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-28 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651503
• 关键词: T cell receptor; T lymphocyte; autoimmunity; cell differentiation; genetic recombination; genetically modified animals; laboratory mouse; leukopoiesis; nuclear receptors; receptor expression; thymus

DESCRIPTION (provided by applicant): The nuclear hormone receptor superfamily is composed of ligand-regulated transcription factors and orphan receptors, for which ligands are not identified or may not exist. These receptors perform extremely diverse functions in development, reproduction, and homeostasis by regulating cell growth, differentiation, and apoptosis. Aberrant activities of some hormone receptors have been causally linked to neoplasia. Recently, studies from our group and others on the orphan nuclear receptors ROR-gamma (Retinoic acid receptor-related Orphan Receptor) and its thymus specific isoform ROR-gamma-t demonstrated that this nuclear receptor regulates the survival and cell cycle status of CD4+CD8+ double-positive thymocyte. However, the role of ROR-gamma-t/ROR-gamma in thymocyte differentiation remains largely unknown. In this proposal, we will perform experiments to determine how ROR-gamma-t/ROR-gamma regulates thymocyte positive and negative selection through the use of animals lacking ROR-gamma-t/ROR-gamma expression. Furthermore, we will examine the regulation of pre-TCRa by ROR-gamma-t in vivo. These experiments will provide important new information regarding the role of ROR-gamma-t and ROR-gamma in thymopoiesis and the molecular basis of thymocyte differentiation. In addition, results from this application will also provide insights for the role of ROR-gamma-t in tumorigenesis.

描述（由申请人提供）：核激素受体超家族 由配体调节的转录因子和孤儿受体组成， 所述配体未被鉴定或可能不存在。这些受体执行 在发育、生殖和体内平衡中具有极其多样的功能， 调节细胞生长、分化和凋亡。的异常活性 某些激素受体与瘤形成有因果关系。最近， 我们小组和其他人对孤儿核受体ROR-γ的研究 视黄酸受体相关孤儿受体及其胸腺特异性 同种型ROR-γ-t表明，这种核受体调节 CD 4 + CD 8+双阳性胸腺细胞存活和细胞周期状态。然而，在这方面， ROR-γ-t/ROR-γ在胸腺细胞分化中作用仍然很大 未知在这个建议中，我们将进行实验，以确定如何 ROR-gamma-t/ROR-gamma调节胸腺细胞的正负选择 通过使用缺乏ROR-γ-t/ROR-γ表达的动物。 此外，我们将在体内检查ROR-γ-t对前TCR α的调节。 这些实验将提供关于 ROR-γ-t和ROR-γ与胸腺细胞的分子基础 分化此外，该应用程序的结果还将提供 ROR-gamma-t在肿瘤发生中的作用。