RAGE and modulation of tumor properties

描述（由申请人提供）： 首席研究员寻求 在有指导的环境中进行高级培训， 晚期糖基化终产物受体（英语：Receptor for Advanced Glycation Endproducts）（RECEPTOR for Advanced Glycation Endproducts） 的 第一个目标是为私人侦探提供一个环境，和她的担保人 大卫斯特恩博士，以获得所需的培训，在正式课程和在 实验室工作台发展成为一个独立的临床科学家。 的 第二个目的是分析在肿瘤细胞的调节中， 特性. 最近的研究表明，表达的cardiac和它的一个 在发育中的神经细胞中， 系统 在体外，Escherin-Escherin相互作用介导了脑细胞的生长， 皮质神经突，因为这一过程被阻断抗体所抑制， 或可溶性β-淀粉样蛋白（saponin），β-淀粉样蛋白的胞外配体结合域。 这些发现，沿着观察到， 肿瘤组织中存在着与肿瘤细胞增殖相关的蛋白质，提示它们可能参与肿瘤的发生发展。 生物学 在小鼠肿瘤模型中，阻断Escherin/Escherin抑制了 MAP激酶家族成员p44/p42、p38和SAPK/JNK的活化， 参与肿瘤细胞增殖、侵袭/迁移和激活 基质金属蛋白酶 在体内，阻断RAGE-白藜芦醇相互作用 抑制从植入的大鼠C6胶质瘤细胞生长的原发性肿瘤，和肺 通过抑制增殖，在荷刘易斯肺癌的小鼠中转移 和侵略性。 在体外，阻断抑制肿瘤细胞生长的促癌素-β 1 细胞增殖、细胞周期蛋白D1表达、侵袭和迁移。 我们推测 肿瘤抑制素调节肿瘤床内的关键特性， 假设在肿瘤细胞被配体如 关键的细胞信号传导通路被激活，有助于肿瘤的发生。 增殖、侵袭、迁移和降解细胞外基质。 我们提出两个具体目标： 1. 来描述信号转导 激活的途径后，从事的研究，和2。 以确定封锁是否 阻止癌前病变的进展。 一系列工具将 为了实现这些目标，无论是在体外试验中， 系统，并在体内，使用numbernull小鼠和小鼠模型的家族性 腺瘤性息肉病（FAP）。

DESCRIPTION (provided by applicant): The Principal Investigator seeks advanced training in a mentored environment to study the contribution of the Receptor for Advanced Glycation Endproducts (RAGE) in tumor biology. The first objective is to provide an environment for the P.I., with her sponsor, Dr. David Stern, to obtain the needed training in formal courses and at the laboratory bench to develop into an independent clinician scientist. The second objective is to dissect the role of RAGE in modulating tumor cell properties. Recent studies indicated that expression of RAGE and one of its ligands, amphoterin, was markedly upregulated in the developing nervous system. In vitro, amphoterin-RAGE interaction mediated outgrowth of cerebral cortical neurites, as the process is inhibited by blocking antibodies to RAGE, or soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE. These findings, along with the observation that enhanced levels of amphoterin and RAGE are present in tumors, suggested their possible contribution to tumor biology. In murine tumor models, blockade of amphoterin/RAGE suppressed activation of members of the MAP kinase family, p44/p42, p38 and SAPK/JNK, involved in tumor cell proliferation, invasion/migration, and activation of matrix metalloproteinases. In vivo, blockade of RAGE-amphoterin interaction suppressed primary tumors grown from implanted rat C6 glioma cells, and lung metastases in mice bearing Lewis lung carcinoma, by suppressing proliferation and invasiveness. In vitro, blockade of amphoterin-RAGE suppressed tumor cell proliferation, expression of cyclin D1, invasion and migration. We speculate that amphoterin-RAGE modulates critical properties within the tumor bed and hypothesize that subsequent to activation of tumor RAGE by ligand such as amphoterin, key cell signaling pathways are activated that contribute to tumor proliferation, invasion, migration and degradation of extracellular matrix. We propose two specific aims: 1. to delineate the signal transduction pathways activated upon engagement of RAGE, and 2. to determine if blockade of RAGE arrests progression of pre-malignant lesions. A range of tools will be employed in order to accomplish these goals, both in in vitro assay systems, and in vivo, using RAGE null mice and a murine model of familial adenomatous polyposis (FAP).