Proj 2: Molecular Imaging of Cell Surface Receptors in Cancer

项目 2：癌症细胞表面受体的分子成像

• 批准号: 7490305
• 负责人: Alnawaz Rehemtulla
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490305
• 关键词: Affect; Animals; Apoptosis; Behavior; Biochemical; Biological Assay; Blood Vessels; Bone Marrow; Breast; CXCR4 Receptors; CXCR4 gene; Cancer Etiology; Cell Proliferation; Cell Surface Receptors; Cells; Cellular Assay; Class; Clinical; Communications Media; Condition; Cultured Cells; Development; Dose; Environment; Enzymes; Epidermal Growth Factor Receptor; Epithelial; Event; Exhibits; Growth; Growth Factor; Head and neck structure; Hepatocyte Growth Factor; Human; Image; In Vitro; Invasive; Life; Ligand Binding; Ligands; Link; Liver; Lung; Malignant Neoplasms; Mediating; Membrane; Modeling; Molecular; Monitor; Mus; Mutation; Nature; Neoplasm Metastasis; Noise; Numbers; Oncogenes; Organ; Outcome; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Physiological Processes; Play; Protein Overexpression; Protein Tyrosine Kinase; Proto-Oncogene Protein c-met; Public Health; Purpose; Receptor Activation; Receptor Inhibition; Recruitment Activity; Reporter; Reporting; Role; Sensitivity and Specificity; Signal Transduction; Signaling Molecule; Site; Solid Neoplasm; Specificity; Stem cells; Stromal Cell-Derived Factor 1; System; Tail; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Treatment Efficacy; Xenograft Model; angiogenesis; autocrine; base; cancer cell; cancer site; cancer therapy; cell transformation; chemokine; extracellular; human MET protein; kinase inhibitor; migration; molecular imaging; mouse model; neoplastic cell; neutralizing antibody; novel; paracrine; receptor; response; small molecule; stable cell line; tumor; tumor xenograft; tumorigenesis; validation studies

PROJECT 2: Cell surface receptors comprise an important class of membrane molecules that form communication links between the extracellular milieu and the cell's interior. In addition, a number of cell surface receptors have been shown to play a significant role in imparting specific phenotypes to transformed cells, for example growth factor independence and metastatic behavior. Non-invasive imaging of receptor activity dynamically in live cells and mouse models would significantly enhance our understanding of the role of these receptors in the etiology of cancer and the response of tumors to therapeutic agents directed against these receptors. For the purpose of this proposal we will focus on three distinct receptors. The epidermal growth factor receptor (EGFR) is often over-expressed and activated in tumors in a ligand independent manner, while the hepatocyte growth factor receptor (Met) is activated in an autocrine manner in that tumor cells express the ligand (HGF) and the receptor (Met) simultaneously thus constitutively activating intracellular signaling cascades. The CXCR7 receptor is activated in a paracrine manner in that specific organs such as bone marrow, lung and liver express SDF, the ligand which through CXCR7 activation results in the spread and growth of metastasis to these sites. In Project 2, we propose to develop molecular imaging strategies to image activity of three receptors that contribute significantly to the transformed phenotype. The proposal is organized in three aims, one for each of the above three receptors. In each of the aims we will develop two independent approaches to image the receptor and the one with the best signal to noise and specificity will be used in further in-vitro validation studies to demonstrate that the reporter faithfully reports on the appropriate molecular events. Lastly, in each of the aims, the appropriate receptor will be used to investigate the efficacy of novel therapies directed against each receptor in a live mouse model and the efficacy of the therapy will be correlated with molecular imaging as a non-invasive surrogate for receptor activity. Public Health: The studies proposed here will result in the development of imaging based mouse models that will facilitate the development and testing of anti-cancer therapies directed against key receptor molecules.

项目2：细胞表面受体包括一类重要的膜分子， 细胞外环境和细胞内部之间的通讯联系。此外，一些细胞 表面受体已经显示在赋予转化的细胞特异性表型中起重要作用 细胞，例如生长因子独立性和转移行为。受体的非侵入性成像 在活细胞和小鼠模型中的动态活性将显著增强我们对 这些受体在癌症病因学和肿瘤对治疗剂的反应中的作用， 对抗这些受体。为了这个建议的目的，我们将集中在三个不同的受体。的 表皮生长因子受体（EGFR）通常在肿瘤中过表达并被激活， 肝细胞生长因子受体（Met）以自分泌方式激活 在同时表达配体（HGF）和受体（Met）肿瘤细胞中， 激活细胞内信号级联。CXCR7受体以旁分泌方式被激活， 特定器官如骨髓、肺和肝表达SDF，SDF是通过CXCR7 活化导致转移瘤扩散和生长到这些部位。在项目2中，我们建议开发 分子成像策略，以成像三种受体的活性，这些受体对 转化表型该提案分为三个目标，分别针对上述三个接受体。 在每一个目标中，我们将开发两种独立的方法来成像受体和一种具有 最佳信噪比和特异性将用于进一步的体外验证研究，以证明 报告者忠实地报告适当的分子事件。最后，在每一个目标中， 受体将用于研究针对肝细胞中每种受体的新疗法的功效。 小鼠模型和疗效的治疗将与分子成像作为一种非侵入性 受体活性替代物。 公共卫生：这里提出的研究将导致基于成像的小鼠模型的发展 这将促进针对关键受体的抗癌疗法的开发和测试， 分子。