Molecular Imaging of Chemokine Receptor Signaling

描述(申请人提供)：摘要在许多常见癌症中，趋化因子受体信号是原发肿瘤生长和器官特异性转移的关键决定因素。特别是，我们的实验室和其他实验室已经证明，趋化因子受体CXCR4和CXCR7在乳腺癌和肺癌的恶性细胞上上调。CXCR4和CXCR7信号显著增加原发肿瘤的负担，促进转移癌细胞的存活和增殖，这些都对患者的生活质量和生存产生不利影响。肿瘤微环境中的趋化因子受体信号是由分泌趋化因子配体的基质细胞启动的。这些配体与肿瘤细胞上的同源受体结合，从而激活控制肿瘤进展和转移的下游效应器。了解趋化因子受体CXCR4和CXCR7的整合功能对于剖析原发癌和转移癌的分子调控以及有效靶向这些受体以改进癌症治疗是至关重要的。ESE成像记者建立在我们对信号通路中蛋白质-蛋白质相互作用成像的专业知识基础上。在目标1中，我们将开发一种荧光素酶互补报告来分析趋化因子配体与乳腺癌细胞上CXCR4和CXCR7的胞外结合。在目标2中，我们将构建一个成像报告系统来定量细胞上的趋化因子受体复合体以及这些复合体在信号传递过程中的变化。最后，Aim 3将开发一种基于支架蛋白2-arrestin的细胞内激活CXCR4和CXCR7的成像报告。这项研究将建立新的成像技术来研究CXCR4和CXCR7在乳腺癌中的整合功能，并在完整细胞和活着的小鼠中建立这些趋化因子受体的治疗靶点。除了目前的研究，这些报告技术有望成为研究整个趋化因子和趋化因子受体家族的通用方法，将这些成像技术的应用扩展到癌症以外的许多疾病。公共卫生相关性：这项研究的意义在于，它将开发新的技术来成像乳腺癌和其他各种常见癌症的细胞间和细胞内信号网络。这些成像记者将促进我们对癌症发生和发展为转移疾病的临床前模型中细胞信号的了解。使用这些成像技术还将极大地提高我们测试和验证新治疗剂的能力，我们预计这将改善癌症患者的治疗。

DESCRIPTION (provided by applicant): Abstract Chemokine receptor signaling is a critical determinant of primary tumor growth and organ-specific metastases in many common cancers. In particular, our laboratory and others have shown that chemokine receptors CXCR4 and CXCR7 are upregulated on malignant cells in breast and lung cancer. CXCR4 and CXCR7 signaling significantly increases primary tumor burden and enhances survival and proliferation of metastatic cancer cells, all of which adversely affect quality of life and survival for patients. Chemokine receptor signaling in the tumor microenvironment is initiated by stromal cells that secrete chemokine ligands. These ligands bind to cognate receptors on tumor cells, thereby activating downstream effectors that control tumor progression and metastasis. Understanding integrated functions of chemokine receptors CXCR4 and CXCR7 is essential for dissecting molecular regulation of primary and metastatic cancer and effectively targeting these receptors to improve cancer therapy. ese imaging reporters build upon our expertise in imaging protein-protein interactions in signaling pathways. In aim 1, we will develop a luciferase complementation reporter to analyze extracellular binding of chemokine ligands to CXCR4 and CXCR7 on breast cancer cells. In aim 2, we will construct an imaging reporter system to quantify chemokine receptor complexes on cells and changes in these complexes during signaling. Finally, aim 3 will develop an imaging reporter for intracellular activation of CXCR4 and CXCR7 based on recruitment of the scaffolding protein 2-arrestin. This research will establish new imaging technologies to investigate integrated functions of CXCR4 and CXCR7 in breast cancer and establish therapeutic targeting of these chemokine receptors in intact cells and living mice. Beyond the current research, each of these reporter technologies is expected to serve as a general method to study the entire family of chemokines and chemokine receptors, extending applications of these imaging techniques to many diseases besides cancer. PUBLIC HEALTH RELEVANCE: The significance of this research is that it will develop new techniques to image intercellular and intracellular signaling networks in breast and a wide range of other common cancers. These imaging reporters will advance our knowledge of cell signaling in pre-clinical models of cancer initiation and progression to metastatic disease. Using these imaging technologies also will greatly improve our ability to test and validate new therapeutic agents, which we anticipate will lead to improved treatments for patients with cancer.