Dysregulation of IGF-1R Translational Control

IGF-1R 翻译控制失调

基本信息

批准号：
8321995
负责人：
SCOTT W BLUME
金额：
$ 24.46万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-18 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321995
关键词：
5&apos Untranslated Regions Affinity Chromatography Animal Model Antineoplastic Agents Apoptotic Base Pairing Binding Sites Biological Biological Assay Bioluminescence Categories Cells Development Doxorubicin Drug Delivery Systems Elements Etoposide Gene Expression Genes Heterogeneous-Nuclear Ribonucleoproteins Human IGF1R gene Image Insulin Receptor Insulin-Like-Growth Factor I Receptor Internal Ribosome Entry Site Lead Left Libraries Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mediating Messenger RNA Metastatic Lesion Metastatic Neoplasm to the Breast Modification Nucleotides Pathway interactions Pattern Property Protein Binding Protein Biosynthesis Proteins Proto-Oncogenes RNA Binding RNA Sequences RNA-Binding Proteins Receptor Signaling Recruitment Activity Regulation Relative (related person)Research Research Design Research Institute Resolution Ribosomal RNA Ribosomes Series Signal Transduction Site Site-Directed Mutagenesis Specimen Structure-Activity Relationship Testing Therapeutic Human Experimentation Time Translational Regulation Translations Tumor Cell Line Untranslated Regions Up-Regulation Xenograft Model base cancer cell cell growth chemotherapeutic agent combinatorial cytotoxic drug efficacy genetic regulatory protein genetically modified cells high throughput screening in vivo inhibitor/antagonist malignant breast neoplasm neoplastic cell novel overexpression prototype small molecule synergism tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The type 1 insulin-like growth factor receptor (IGF1R) is a potent proto-oncogene implicated in the development and progression of a large number of human malignancies through its powerful mitogenic, anti- apoptotic, and transforming activities. Our lab has determined that IGF1R gene expression is regulated at the translational level through an internal ribosome entry site (IRES) contained within the 5'-untranslated region of the mRNA. Our research has focused on determining how the IRES operates, how it is regulated by sequence-specific RNA-binding proteins, and how these molecules and mechanisms may be altered in cancer. Our results led us to hypothesize that a small molecule inhibitor of the IGF1R IRES could be developed which could be used to specifically block IGF1R protein synthesis and thereby reverse the survival / proliferative advantage associated with IGF1R overexpression in tumor cells. An IRES-targeted drug potentially represents a gene-specific translational inhibitor, with enormous potential utility, both for research and therapeutic applications. Toward this objective, we have initiated a major collaborative effort with Southern Research Institute to perform a high throughput screen of a 125,000 compound library to identify compounds capable of inhibiting translation mediated through the IGF1R IRES. The Specific Aims are: 1. Utilize a series of mechanistic and functional biological assays to characterize the IRES inhibitors emanating from the high throughput screen, analyzing the consequences for IGF1R signaling while leaving insulin receptor signaling intact, and assessing the potential of these compounds to induce favorable phenotypic changes in breast tumor cells, including decreased capacity for clonogenic proliferation and enhanced sensitivity to cytotoxic chemotherapeutic agents. 2. Test the anti-tumor and anti-metastatic efficacy of the most promising IRES inhibitors in animal models, using serial in vivo bioluminescence imaging to correlate changes in IRES activity with progression or regression of the tumor in real time. 3. Perform iterative synthetic modifications to selected lead compounds emerging from the compound progression pathway, coordinated with biological re-testing and structure-activity relationship analyses, to optimize efficacy and drug-like properties of the IRES inhibitors. 4. Investigate the manner in which the newly identified IGF1R IRES-regulatory proteins (ITAFs) collectively modulate IGF1R translational efficiency, how the RNA-binding activities of these IRES- regulatory proteins may be altered in primary human breast tumors and metastatic lesions, and how specific interactions between these IRES-regulatory proteins, the IGF1R IRES, and the 40S ribosome may be blocked by the small molecule IRES inhibitors.

描述（由申请人提供）：1型胰岛素样生长因子受体（IGF1R）是一种有效的原始癌细胞，与其强大的有丝分裂，抗凋亡和转化活性有关大量人类恶性肿瘤的发展和发展。我们的实验室已经确定，IGF1R基因表达通过在mRNA的5'-非翻译区域内包含的内部核糖体入口位点（IRES）调节。我们的研究重点是确定IRES如何工作，如何通过序列特异性RNA结合蛋白调节，以及这些分子和机制如何在癌症中改变。我们的结果导致我们假设可以开发IGF1R IRES的小分子抑制剂，该抑制剂可用于特异性阻断IGF1R蛋白合成，从而逆转与肿瘤细胞中IGF1R过表达相关的存活 /增殖优势。针对IRES的药物可能代表一种基因特异性的转化抑制剂，具有巨大的潜在效用，无论是用于研究和治疗应用。为了实现这一目标，我们已经与南方研究所（Southern Research Institute）进行了一项重大合作，以进行125,000个复合库的高吞吐量屏幕，以识别能够抑制通过IGF1R IRES介导的翻译的化合物。具体目的是：1。利用一系列的机械和功能生物学测定来表征来自高吞吐量筛查发出的IRES抑制剂，分析对IGF1R信号传导的后果，同时使胰岛素受体信号完整，并使这些化合物的潜力降低，以诱导这些化合物的潜力，以增强乳腺肿瘤的效果，并促进乳腺肿瘤细胞的变化。细胞毒性化学治疗剂。 2。使用体内生物发光成像，测试最有希望的IRES抑制剂的抗肿瘤和抗转移性功效，以将IRES活性的变化与实时的肿瘤的进展或回归相关联。 3。对从化合物进展途径出现的选定铅化合物进行迭代合成修饰，并与生物学重新测试和结构活性关系分析协调，以优化IRES抑制剂的功效和类似药物样性能。 4.研究新近鉴定的IGF1R调节蛋白（ITAF）的方式共同调节IGF1R的转化效率，这些IRES调节蛋白的RNA结合活性如何在原发性人类乳腺肿瘤和转移性病变中以及这些IRES-ires-ribore-ribore iige and Ire iige1 iigf igffore，iigfore 1 igf igfif中的特定相互作用中如何改变被小分子IRES抑制剂阻塞。