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REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2

血栓烷A2对胸腺细胞凋亡的调节

基本信息

批准号：
6169407
负责人：
ROSLYN B MANNON
金额：
$ 2.67万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-04-01 至 2000-06-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6169407
关键词：
T lymphocyte apoptosis autoimmunity biological signal transduction cell differentiation genetically modified animals immune tolerance /unresponsiveness laboratory mouse organ culture receptor receptor expression thromboxanes thymus

项目摘要

DESCRIPTION: Training Plan: The clonal deletion of autoreactive thymocytes (negative selection) results from the induction of programmed cell death or apoptosis. This process is important for achieving tolerance within an individual. While loss of self-tolerance may result in autoimmune disease, the induction of tolerance to alloantigens may result in permanent organ graft acceptance. Recent studies suggest that thromboxane A2 (TxA2) produced in the thymic microenvironment may regulate thymic maturation. Thromboxane synthase, the final catalytic enzyme involved in TxA2 synthesis, is expressed within the thymus. Moreover, the thymus expresses high levels of the thromboxane receptor (TxR), far above that of other tissues tested. Finally, TxR expression has been localized to immature thymocytes and exposure of these cells to TxA2 induces apoptosis. Therefore, the hypothesis is that TxA2 binds to its receptor and, through specific signaling pathways, regulates cellular processes important to T cell maturation and selection. The goals of this project are to identify the biochemical characteristics and ontogeny of the TxR in thymocytes and identify the function of TxA2 in thymocyte development. To investigate this hypothesis, three specific aims are proposed: (1) To characterize the signal transduction pathways coupled to the TxR in thymocytes. In these studies, the signal transduction pathways coupled to the TxR in freshly isolated thymocytes will be identified by microphysiometry and active second messenger coupling confirmed by standard biochemical assays. (2) To identify which signals activated by TxR cause apoptosis in thymocytes. These studies will directly determine which of the second messengers (identified in specific aim I) mediate apoptosis of thymocytes in vitro. (3) To define the effects of TxA2 on thymocyte maturation in vitro. Using fetal thymic organ culture as a model of thymic development, the applicant will directly test the role of TxA2 in influencing the development of T cells. T cell receptor transgenic mice will be used to specifically examine the role of TxA2 in controlling negative selection of autoreactive T cell precursors. This project is expected to provide novel information regarding the expression and function of the TxR in thymocytes and the effective role of TxA2 in regulating T cell maturation. It is hoped that understanding of the role of lipid mediators in the thymic development may suggest new strategies in preventing autoimmune disease and in the induction of transplantation tolerance to organ allografts.

说明：训练计划：自身反应性胸腺细胞的克隆性删除(阴性选择)由诱导细胞程序性死亡或细胞凋亡。这一过程对于在个人的。而丧失自我耐受性可能会导致自身免疫疾病，诱导对同种异体抗原的耐受可能导致永久性器官移植接受。最近的研究表明，血栓素胸腺微环境产生的A2(TXA2)可能调节胸腺成熟。血栓烷合成酶，参与其中的最后一种催化酶在TXA2合成中，在胸腺中表达。此外，胸腺表达高水平的血栓烷受体(TxR)，远远高于其他被测试的组织。最后，TxR表达式已本地化为未成熟胸腺细胞和暴露于TXA2诱导细胞凋亡。因此，假设TXA2与其受体结合，并通过特定的信号通路，调节重要的细胞过程 T细胞的成熟和选择。该项目的目标是鉴定TxR的生化特性和个体发育并确定TXA2在胸腺细胞发育中的作用。为了研究这一假说，提出了三个具体目标：(1) 为了表征与TxR偶联的信号转导通路胸腺细胞。在这些研究中，信号转导通路耦合在新鲜分离的胸腺细胞中对TxR的结合将通过显微生理学和活跃的第二信使偶联标准的生化分析。(2)识别哪些信号是由 TxR可引起胸腺细胞的凋亡。这些研究将直接确定第二个信使中的哪一个(在具体目标一中确定)进行调解胸腺细胞在体外的凋亡。(3)明确血栓素A_2对胸腺细胞在体外成熟。利用胎儿胸腺器官培养作为一种胸腺发育模型，申请者将直接测试其作用 TXA2在影响T细胞发育中的作用。T细胞受体转基因小鼠将被用来专门检测TXA2在控制自身反应性T细胞前体的阴性选择。该项目预计将提供有关 TxR在胸腺细胞中的表达、功能及其作用 TXA2在调节T细胞成熟中的作用。希望能够理解脂质介质在胸腺发育中的作用可能提出新的预防自身免疫性疾病的策略和诱导移植对同种异体器官的耐受性。