RAGE and modulation of tumor properties

描述(由申请人提供)：首席调查员寻求 在有指导的环境中进行高级培训，以研究 肿瘤生物学中的晚期糖基化终产物受体(RAGE)这个 第一个目标是为私家侦探和她的赞助人提供一个环境， 大卫·斯特恩博士，要在正规课程和 实验室工作台要发展成为独立的临床医生科学家。这个 第二个目标是剖析RAGE在调节肿瘤细胞中的作用。 属性。最近的研究表明，RAGE及其其中之一的表达 配基，两性霉素，在发育中的神经中显著上调。 系统。两性激素-RAGE相互作用在体外介导的脑生长 皮质神经突起，因为这一过程被阻止RAGE的抗体所抑制， 或可溶性RAGE(SRAGE)，RAGE的细胞外配体结合域。 这些发现，以及两性霉素水平升高的观察结果 和RAGE存在于肿瘤中，提示它们可能对肿瘤有贡献 生物学。在小鼠肿瘤模型中，两性霉素/RAGE的阻断受到抑制 MAP激酶家族成员p44/p42、p38和SAPK/JNK的激活， 参与肿瘤细胞的增殖、侵袭/迁移和激活 基质金属蛋白酶。在体内，阻断RAGE-两性霉素相互作用 抑制从移植的大鼠C6胶质瘤细胞和肺中生长的原发肿瘤 通过抑制增殖抑制Lewis肺癌小鼠的转移 和侵犯性。两性霉素受体阻滞剂对肿瘤细胞的体外抑制作用 细胞增殖、细胞周期蛋白D1表达、侵袭和迁移。我们推测 两性激素调节肿瘤床内的关键性质，并 假设在激活肿瘤后，配体如 两性霉素，关键细胞信号通路被激活，与肿瘤有关 细胞外基质的增殖、侵袭、迁移和降解。 我们提出了两个具体的目标：1.描述信号转导 在愤怒交战时激活的通路，以及2.确定是否封锁 阻止癌前病变的进展。一系列工具将 为了实现这些目标，在体外试验中 系统，并在体内使用RAGE零基因小鼠和家族性小鼠模型 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).