Genetic Analy. of Chemokine Receptors in T Cell Develop.

遗传分析。

基本信息

批准号：
6571381
负责人：
Lishan Su
金额：
$ 18.05万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2004-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to elucidate the role and regulation of chemokines and chemokine receptors (CKR) that are involved in the intrathymic migration and maturation of hematopoietic progenitor cells (HSPC)/thymocytes, in normal and HIV-1 infected thymus organs. The thymus has 4 distinct regions where progenitor cells and thymocytes at distinct maturation stages reside. HSPC home to the thymus and migrate from the subcapsular region to the cortex, cortical-medullary junction (CMJ), and to the medulla as they mature. The mechanism of thymocyte migration during maturation in the thymus is not clear. Multiple chemokines (SDF-1, TECK, MDC, IP-10, and ELC) and corresponding CKR (CXCR4, CCR9, CCR4, CXCR3 and CCR7) are expressed in the thymus. We recently discovered that HIV-1 infection of the thymus (or gpl20 interaction with CD4 and CXCR4 or CCR5) led to induction of IP-10 (a ligand of CXCR3). We hypothesize that specific chemokines in specific regions of the thymus are involved in the specific thymocyte migration and maturation. We have recently developed a novel genetic system to inhibit expression and function of CKR with a specific chemokine fused to the HIV-1 Vpu domain that traps and degrades the CKR in the ER (degrakines). We propose to optimize the degrakine system to define and characterize the CKR on HSPC/thymocyte cells that are required for their migration and maturation in the thymus. The findings will shed light on our understanding of the thymus function and of HIV-1 pathogenesis in the thymus. Specifically, we will develop a novel genetic system to define CKR involved in thymocyte migration and maturation in the thymus. By the end of the project, we will 1) create novel "Degrakines" that target most or all of the CKR with known CK ligands expressed in the thymus. 2) We will define the functions of CXCR3, CXCR4, CCR4, CCR7 and CCR9 in thymocyte migration and maturation in the human thymus. Therefore, findings from this highly novel (both in concept and technology) R21-project will open new avenues in understanding the biology of CK/CKR in the thymus, as well as in furthering our understanding of HIV- 1 pathogenesis in the thymus. The parental RO1 grant (AI41356) proposed to 1) define the HIV-1 pathogenic factors which induce thymocyte depletion in the human thymus and 2) determine the mechanisms of the "pathogenic factors" mediating thymus depletion. In addition to the IP-10 and CXCR3 functions implicated in HIV-1 pathogenesis in the thymus, the degrakines will be useful for the study of HIV- 1 pathogenesis in the thymus to capitalize on the novel genetic system and to augment the value of the parental grant.

描述（由申请人提供）：该提案的长期目标是阐明参与正常和HIV-1感染的胸腺胸腺胸腺细胞的趋化因子和趋化因子受体（CKR）（CKR）（CKR）的作用和调节。胸腺具有4个不同的区域，其中祖细胞和胸腺细胞处于不同成熟阶段。 HSPC居住在胸腺的家中，并从囊下区域迁移到皮层，皮质 - 甲状腺结局（CMJ），并随着成熟而迁移到髓质。胸腺成熟过程中胸腺细胞迁移的机制尚不清楚。多个趋化因子（SDF-1，Teck，MDC，IP-10和ELC）和相应的CKR（CXCR4，CCR9，CCR4，CXCR3和CCR7）在胸腺中表达。我们最近发现，胸腺的HIV-1感染（或与CD4和CXCR4或CCR5相互作用）导致IP-10诱导（CXCR3的配体）。我们假设胸腺特定区域的特定趋化因子参与了特定的胸腺细胞迁移和成熟。我们最近开发了一种新型的遗传系统，用融合到HIV-1 VPU结构域的特定趋化因子抑制CKR的表达和功能，该趋化因子陷入了ER中的CKR并降解CKR（Degrakines）。我们建议优化脱脂系统，以定义和表征其在胸腺中迁移和成熟所需的HSPC/胸腺细胞细胞上的CKR。这些发现将阐明我们对胸腺中胸腺功能和HIV-1发病机理的理解。具体而言，我们将开发一个新型的遗传系统，以定义与胸腺中胸腺细胞迁移和成熟有关的CKR。到项目结束时，我们将1）创建针对大多数或全部CKR的新颖的“脱脂型”，其用胸腺中表达的已知CK配体。 2）我们将定义人胸腺中胸腺细胞迁移和成熟的CXCR3，CXCR4，CCR4，CCR7和CCR9的功能。因此，从这种高度新颖的（在概念和技术方面）R21项目中的发现将开辟新的途径，以理解胸腺中CK/CKR的生物学，并进一步了解我们对胸腺中HIV-1发病机理的理解。父母RO1赠款（AI41356）提出了1）定义诱导人胸腺中胸腺细胞耗竭的HIV-1致病因子和2）确定介导胸腺消耗的“致病因子”的机制。除了与胸腺中HIV-1发病机理有关的IP-10和CXCR3功能外，脱脂林还将有助于研究胸腺中HIV-1发病机理，以利用新的遗传系统并增强父母赠款的价值。