Regulation of Chemokine Mediated Leukocyte Functions

描述（由申请方提供）：趋化因子是炎症介质 许多细胞的趋化和细胞毒性功能 包括嗜中性粒细胞、单核细胞、嗜酸性粒细胞、嗜碱性粒细胞和淋巴细胞。这些 通过与特定细胞表面的相互作用启动功能 G蛋白偶联受体（GPCR）。大多数趋化因子激活不止一种 白细胞上的受体。这一应用的基础假设是， 由于多种趋化因子存在于炎症部位， 必须严格调节受体活性以防止组织损伤。我们 已经开发了一种细胞模型，大鼠嗜碱性白血病细胞系（RBL-2 H3）， 其中趋化因子受体可以单独或多次表达， 许多白细胞活动。这些研究提供了惊人的证据， 这些受体相互交叉调节的功能在多个步骤。信号 持续时间和蛋白激酶C（PKC）激活已被证明是至关重要的 用于受体交叉调节。吞噬细胞和小鼠模型的研究 腹膜和皮肤炎症显示出交叉调节的复杂性 白细胞介素-8（IL-8）和RANTES。这种复杂性可能反映了 这些趋化因子激活白细胞中多种受体的能力。的 本申请的总体目标是阐明 IL-8受体（CXCR 1和CXCR 2）和RANTES之间的交叉调节 (CCR1和CCR 5），并鉴定信号传导中的特异性分子靶标。 途径，调节其介导和经历 交叉脱敏交叉脱敏的机制将被调查 通过确定不同蛋白激酶C（PKC）同工酶在 受体交叉磷酸化。抑制素介导的受体 还将在β抑制蛋白中测试内化调节信号持续时间 缺陷小鼠 趋化因子参与许多急性和慢性炎性疾病， 类风湿性关节炎、肺气肿、囊性纤维化、慢性支气管炎和 支气管扩张和肿瘤恶性黑色素瘤细胞增殖。 了解趋化因子调控的分子机制 将有助于了解炎症的控制以及病因 许多炎症性疾病的症状这些研究还将确定具体的 用于开发治疗药物以调节 炎症

DESCRIPTION (provided by the applicant): Chemokines are inflammatory mediators of the chemotactic and cytotoxic functions of a large variety of cells including neutrophils, monocytes, eosinophils, basophils and lymphocytes. These functions are initiated through interaction with specific cell surface G-protein coupled receptors (GPCRs). Most chemokines activate more than one receptor on leukocytes. The hypothesis that underlies this application is that since multiple chemokines are present at sites of inflammation, the chemokine receptors activities must be tightly regulated to prevent tissue damage. We have developed a cellular model, a rat basophilic leukemia cell line (RBL-2H3), in which chemokine receptors can be singly or multiply expressed to display many leukocytes activities. These studies have provided striking evidence that these receptors cross-regulate each other?s function at multiple steps. Signal duration and protein kinase C (PKC) activation have been shown to be critical for receptor cross-regulation. Studies in phagocytes and mouse models of peritoneal and skin inflammation have shown a complexity of cross-regulation among interleukin-8 (IL-8) and RANTES. This complexity likely reflects the ability of these chemokines to activate multiple receptors in leukocytes. The overall objective of this application is to elucidate the mechanism(s) of cross-regulation among the receptors for IL-8 (CXCR1 and CXCR2) and RANTES (CCR1 and CCR5) and to identify specific molecular targets in the signaling pathways, which modulate their ability to mediate and undergo cross-desensitization. Mechanisms of cross-desensitization will be investigated by determining the role of different protein kinase C (PKC) isozymes in receptor cross-phosphorylation. The hypothesis that arrestin-mediated receptor internalization modulate signal duration will also be tested in beta arrestin deficient mice. Chemokines are involved in many acute and chronic inflammatory diseases such as rheumatoid arthritis, emphysema, cystic fibrosis, chronic bronchitis and bronchiectasis and proliferation of tumor malignant melanoma cells. Understanding the molecular mechanisms governing the regulation of chemokine will aid in understanding the control of inflammation as well as the etiology of many inflammatory disorders. These studies will also identify specific targets for the development of therapeutic drugs for the modulation of inflammation.