Components of Translation in Signal Transduction

信号转导翻译的组成部分

基本信息

批准号：
8825431
负责人：
PAUL R SCHIMMEL
金额：
$ 29.93万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825431
关键词：
Alternative Splicing Amino Acids Amino Acyl-tRNA Synthetases Aminoacylation Animals Antineoplastic Agents Binding Biological Assay Blood Vessels Cadherins Cells Chemical Agents Clinical Treatment Clinical Trials Combined Modality Therapy Complex Dependency Docking E-Cadherin Equilibrium Etiology Eukaryota Evolution Foundations Gene Activation Human In Vitro Intercellular Junctions Interferons Lead Length Ligase Malignant Neoplasms Melanoma Cell Metastatic Neoplasm to the Lung Modeling Molecular Monoclonal Antibodies Mus Mutant Strains Mice N-terminal Names Neurons Physiological Property Protein Biosynthesis Proteins Proteolysis RNA Reaction Research Personnel Resolution Signal Transduction Solid Structure Testing Therapeutic Time Transfer RNA Translations Tryptophan-tRNA Ligase Variant Vision Work Xenograft procedure Zinc angiogenesis anti-cancer therapeutic antiangiogenesis therapy base blood vessel development cadherin 5 cancer therapy cell type cytokine design dimer in vitro activity in vivo interest melanoma monomer mouse model novel novel strategies oncology research study response small molecule success therapeutic protein tumor

项目摘要

DESCRIPTION (provided by applicant): This project focuses on the establishment of a new class of natural proteins as therapeutics for treatment of cancers. Specific aims for the next period focus on providing a solid foundation for advancing a first-in-class biologic into human clinical trials for treatment of malignant melanoma. The application is based on the novel, expanded function of an activated form of a human tRNA synthetase and its applications to oncology. The synthetases (one for each amino acid) are ancient, universal proteins that catalyze attachment (aminoacylation) of each amino acid to its cognate tRNA in the first step of protein synthesis. We focused on the ex-translational function of a specific tRNA synthetase-tryptophanyl tRNA synthetase--where physiological relevance is clear. A naturally produced alternative form of human TrpRS, named as TrpRSAct, has potent anti-angiogenic activity through a mechanism that has been worked out in some detail. In particular, it blocks the assembly of new blood vessels and simultaneously inhibits activation of genes associated with angiogenesis. Because it inhibits new blood vessel formation, with no disruption of existing blood vessels, TrpRSAct has appeal for therapeutic applications to oncology. In addition to its strong anti-angiogenic properties, preliminary work showed that exogenously provided TrpRSAct activates destruction of a cellular protein that is involved in the etiology of many cancers, and is the target of new anti-cancer therapeutics. Preliminary work showed a strong therapeutic response to TrpRSAct when administered to mice bearing two different melanomas. The concepts and new treatments that emerge from this work are intended to change and expand the perspective and vision of investigators who focus on developing new approaches to cancer treatment. Specifically, while virtually all approaches to cancer therapies rely on small molecule chemotherapeutics or monoclonal antibodies, the proposed work introduces an entirely new first-in-class therapeutic protein. In addition, because the mechanism of action of TrpRSAct is distinct from those of the approved chemotherapeutics or monoclonal antibodies, it may be used in combination with existing therapeutics. Preliminary studies show strong activity of TrpRSAct when used alone, or in combination with a chemical agent. This success of the combination is doubtless because the mechanism of action of TrpRSAct is different. Thus, beyond the use by itself, TrpRSAct could lead to many new and expanded combination therapies.

描述（由申请人提供）：该项目的重点是建立一类新的天然蛋白质作为治疗癌症的疗法。下一阶段的具体目标是为将一流的生物制剂推进治疗恶性黑色素瘤的人体临床试验提供坚实的基础。该应用基于人类 tRNA 合成酶激活形式的新颖扩展功能及其在肿瘤学中的应用。合成酶（每个氨基酸一个）是古老的通用蛋白质，在蛋白质合成的第一步中催化每个氨基酸与其同源 tRNA 的附着（氨酰化）。我们重点关注特定 tRNA 合成酶（色氨酸 tRNA 合成酶）的翻译外功能，其生理相关性很明确。人类 TrpRS 的一种自然产生的替代形式被命名为 TrpRSAct，通过已详细研究的机制具有有效的抗血管生成活性。特别是，它阻止新血管的组装，同时抑制与血管生成相关的基因的激活。由于它能抑制新血管形成，且不会破坏现有血管，因此 TrpRSAct 在肿瘤学治疗应用中具有吸引力。除了其强大的抗血管生成特性外，初步研究表明，外源提供的 TrpRSAct 还可激活细胞蛋白的破坏，该蛋白参与许多癌症的病因学，并且是新抗癌疗法的目标。初步研究表明，当给患有两种不同黑色素瘤的小鼠施用 TrpRSAct 时，它会产生强烈的治疗反应。这项工作中出现的概念和新疗法旨在改变和扩大专注于开发癌症治疗新方法的研究人员的视角和愿景。具体来说，虽然几乎所有癌症治疗方法都依赖于小分子化疗药物或单克隆抗体，但拟议的工作引入了一种全新的一流治疗蛋白。此外，由于TrpRSAct的作用机制与已批准的化疗药物或单克隆抗体不同，因此它可以与现有的治疗药物联合使用。初步研究表明，TrpRSAct 单独使用或与化学试剂结合使用时具有很强的活性。此次组合的成功无疑是因为TrpRSAct的作用机制不同。因此，除了单独使用之外，TrpRSAct 还可以带来许多新的和扩展的联合疗法。