REGULATION OF HIV1 CORECEPTORS CXCR4

趋化因子是趋化性细胞因子的多样化基因家族， 调节白细胞的迁移和激活，通过与 细胞表面G蛋白偶联受体。 他们在这方面发挥着重要作用， 许多炎性疾病的病理生理学 关节炎、哮喘和其他肺部疾病。 最近，趋化因子 受体CCR 5或CXCR 4被鉴定为 人类免疫缺陷病毒HIV-1进入CD 4阳性细胞。 虽然CCR 5是主要病毒进入的目标，但CXCR 4可能是 在从无症状感染发展为艾滋病的过程中起重要作用。我们 已经开发出了新的细胞模型， 趋化因子受体的调节机制。趋化因子受体 包括CXCR 4在大鼠嗜碱性白血病中功能性表达 细胞系（RBL-2 H3），其显示许多白细胞活性。 这些 研究提供了趋化因子受体交叉调节 在多个层面上发挥各自的作用。 本提案的总体目标是， 使用RBL-2 H3的CXCR 4信号传导、脱敏和内化 模型系统 磷酸化在信号传导中的作用 在RBL-细胞中稳定地测定受体的脱敏 表达表位标记的天然或突变的CXCR 4。 结构性 受体上调节内化的元素将被 鉴定 CXCR 4受体与T嗜性HIV-1包膜的相互作用 糖蛋白（GP 120）及其衍生肽的研究。 其他趋化因子受体和粘附分子 调节CXCR 4功能，反之亦然。 横 趋化因子受体的调节沿着差异表达可 是导致病理性白细胞选择性聚集的原因， 条件和细胞类型特异性。 理解 调节CXCR 4的机制将提供新的靶点， 对HIV-1感染者进行治疗性干预的更好理由 个体和其他炎性疾病中。

The Chemokines are a diverse gene family of chemotactic cytokines that regulate the migration and activation of leukocytes by interacting with cell-surface G-protein coupled receptors. They play a major role in the pathophysiology of many inflammatory disorders such as rheumatoid arthritis, asthma and other lung diseases. Recently, chemokine receptors CCR5 or CXCR4 were identified as essential co-receptors for the entry of human immunodeficiency virus HIV-1 into CD4 positive cells. While CCR5 is the target for the entry of primary viruses CXCR4 may be important in the progression to AIDS from asymptomatic infection. We have developed novel cellular models for understanding the molecular mechanisms of regulation of chemokine receptors. Chemokine receptors including CXCR4 are functionally expressed in a rat basophilic leukemia cell line (RBL-2H3) which displays many leukocyte activities. These studies have provided evidence that chemokine receptors cross-regulate each other's functions at multiple levels. The overall objective of this proposal is to delineate the pathways of CXCR4 signaling, desensitization and internalization using the RBL-2H3 model system. The role of phosphorylation in signaling and desensitization of the receptors will be determined in RBL-cells stably expressing epitope-tagged native or mutated CXCR4. The structural elements on the receptors that regulate internalization will be identified. Interaction of CXCR4 receptors with T-tropic HIV-1 envelope glycoprotein (GP120) and the peptides derived from it will be studied. The mechanisms by which other chemokine receptors and adhesion molecules regulate CXCR4 function and vice versa will be investigated. Cross regulation of chemokine receptors along with differential expression may be responsible for selective leukocyte accumulation in pathological conditions and cell type specificity in viral infection. Understanding the mechanism by which CXCR4 is regulated will provide novel targets and better rationale for therapeutic intervention in HIV-1 infected individuals and in other inflammatory disorders.