INHIBITION OF IGF MEDIATED TUMORIGENESIS

抑制 IGF 介导的肿瘤发生

• 批准号: 6710662
• 负责人: STEVEN Alan ROSENZWEIG
• 金额: $ 25.74万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710662
• 关键词: affinity labeling; binding proteins; binding sites; biotin; carcinogenesis inhibitor; chemical models; drug design /synthesis /production; growth factor receptors; insulinlike growth factor; intermolecular interaction; laboratory rabbit; mass spectrometry; molecular chaperones; molecular dynamics; peptide library; phage display; protein structure function; recombinant proteins; site directed mutagenesis; tissue /cell culture

The insulin-like growth factor 1 (IGF-1 receptor (IGF-1R) is an essential regulator of cell growth and transformation. IGF-1 and IGF-2, via the IGF-1R, are potent breast cancer cell mitogens that promote the tumorigenic potential of cancer cells. The objective of this proposal is to develop reagents that block IGF-1R signaling. The insulin-like growth factor binding proteins (IGFBPs) bind IGF-1 and IGF-2 with higher affinities than the IGF-1R and serve to both protect the IGFs from degradation and reduce their delivery to the IGF-1R. The hypothesis of the proposal is that blockade of IGF-1R activity can be accomplished by developing IGF antagonists based on the structure of the IGF binding domain on the IGFBPs. The goal of Aim 1 is to define the structure of the IGF-binding domain on rhIGFBP-2 using photoaffinity labeling and mass spectrometric analyses. To this end, IGF-1 derivatized with photactivatable groups within its IGFBP-binding domain will be synthesized. This will allow the precise identification of the sites of interaction between rhIGFBP-2 and IGF-1. Based on these analyses, deletion, truncation and site-directed mutants of IGFBP-2 will be generated and tested for IGF binding activity. Aim 2 will characterize the structure and function of a 15.8 kDa fragment of IGFBP-2. The goal of Aim 3 is to examine the mechanism responsible for IGFBPP-2 inhibition of IGF action. The goal of Aim 4 is to employ phage display to screen libraries for peptides having a high affinity for the IGFBP-binding domain on IGF-1 as an alternative means of designing IGF antagonists.

胰岛素样生长因子 1（IGF-1 受体 (IGF-1R) 是一种 细胞生长和转化的重要调节剂。 IGF-1 和 IGF-2，通过 IGF-1R 是有效的乳腺癌细胞有丝分裂原，可促进肿瘤发生 癌细胞的潜力。该提案的目标是开发 阻断 IGF-1R 信号传导的试剂。胰岛素样生长因子结合 蛋白质 (IGFBP) 与 IGF-1 和 IGF-2 的结合亲和力高于 IGF-1R 并起到保护 IGF 免遭降解并减少其递送的作用 至IGF-1R。该提案的假设是 IGF-1R 的阻断 活性可以通过开发IGF拮抗剂来实现 IGFBP 上 IGF 结合域的结构。目标 1 的目标是 使用光亲和力定义 rhIGFBP-2 上 IGF 结合域的结构 标记和质谱分析。为此，IGF-1 衍生化为 将合成其 IGFBP 结合域内的光激活基团。 这将允许精确识别之间的相互作用位点 rhIGFBP-2 和 IGF-1。基于这些分析，删除、截断和 将生成 IGFBP-2 的定点突变体并测试 IGF 结合 活动。目标 2 将表征 15.8 kDa 的结构和功能 IGFBP-2 的片段。目标 3 的目标是检查负责的机制 用于 IGFBPP-2 抑制 IGF 作用。目标 4 的目标是利用噬菌体 展示以筛选具有高亲和力的肽库 IGF-1 上的 IGFBP 结合域作为设计 IGF 的替代方法 对手。