Differential mechanisms for RORgammat-regulated thymocyte development and Th17 di

RORgammat 调节胸腺细胞发育和 Th17 di 的差异机制

• 批准号: 8810643
• 负责人: Zuoming Sun
• 金额: $ 42万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810643
• 关键词: Affect; Arthritis; Autoimmune Diseases; Autoimmunity; Biological Process; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Chromatin; Collaborations; Data; Development; Diabetes Mellitus; Drug Targeting; Gene Expression; Gene Targeting; Goals; Health; Helper-Inducer T-Lymphocyte; Immune response; Interleukin-17; Lymphoid Tissue; Lymphoma; Mediating; Modeling; Molecular Profiling; Multiple Sclerosis; Orphan; Peripheral; Pharmaceutical Preparations; Play; Process; Proteins; Recruitment Activity; Regulation; Role; Signal Transduction; Signaling Molecule; Staging; T cell differentiation; T cell transcription factor 1; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymic Lymphoma; Thymocyte Development; Thymus Gland; Tretinoin; Work; drug development; epigenetic marker; genome-wide; in vivo; innovation; mutant; novel; receptor; thymocyte; tool; transcription factor

DESCRIPTION (provided by applicant): To become competent effector Th17 cells mediating the actual immune responses, T cells have to undergo two ROR?t-dependent differentiation processes sequentially carried out in thymus and peripheral lymphoid tissues. ROR?t is up-regulated in thymocyes to enhance the survival required for completion of T cell maturation process in thymus, and absence of ROR?t activity severely impairs thymocyte development that eventually leads to lymphoma. ROR?t is again up-regulated in peripheral CD4+ T cells to instruct the differentiation of Th17 cells that mediate many types of autoimmunity. ROR?t is thus considered an important drug target for treatment of Th17-dependent autoimmunity. However, little is known about the common and distinct mechanisms that ROR?t utilize to regulate these two differentiation processes. Our goal is to understand the function of ROR?t in both thymocytes and Th17 cells, which will facilitate to develop drugs specifically targeting Th17-dependent autoimmunity, but not interfering with thymocyte development that leads to lymphoma. The objective of this application is to understand how both thymocytes and peripheral T cells differentially use the same transcription factor ROR?t to regulate their differentiation processes.

描述（由申请人提供）：为了成为介导实际免疫应答的有效效应Th17细胞，T细胞必须经历两次ROR？T依赖性分化过程在胸腺和外周淋巴组织中依次进行。吼？t在胸腺细胞中上调，以提高完成胸腺中T细胞成熟过程所需的存活率，而ROR？t活性严重损害胸腺细胞发育，最终导致淋巴瘤。吼？T细胞在外周CD4+ T细胞中再次上调，以指导介导多种类型自身免疫的Th17细胞的分化。吼？因此，T细胞被认为是治疗Th17依赖性自身免疫的重要药物靶标。然而，鲜为人知的是，共同的和独特的机制，ROR？t用于调节这两个分化过程。我们的目标是了解ROR的功能。t胸腺细胞和Th17细胞，这将有助于开发特异性靶向Th17依赖性自身免疫的药物，但不干扰胸腺细胞发育，导致淋巴瘤。本申请的目的是了解胸腺细胞和外周T细胞如何差异地使用相同的转录因子ROR？t来调节它们的分化过程。