Components of Translation in Signal Transduction

描述(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集中在为推进一流的生物学进入人类治疗恶性黑色素瘤的临床试验提供坚实的基础。该应用是基于人tRNA合成酶激活形式的新的、扩展的功能及其在肿瘤学中的应用。合成酶(每个氨基酸一个)是一种古老的、通用的蛋白质，在蛋白质合成的第一步催化每种氨基酸与其同源tRNA的连接(氨基酰化)。我们重点研究了一种特定的tRNA合成酶-色氨酰tRNA合成酶的外翻译功能--其中生理相关性是明确的。一种自然产生的人类TrpRS的替代形式，被称为TrpRSAct，通过一种已经被详细研究出来的机制具有强大的抗血管生成活性。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TrpRSAct在不破坏现有血管的情况下抑制新血管的形成，因此在肿瘤学的治疗应用中具有吸引力。除了其强大的抗血管生成特性外，初步工作表明，外源性提供的TrpRSAct激活了一种与许多癌症的病因有关的细胞蛋白质的破坏，并且是新的抗癌疗法的靶点。初步工作显示，TrpRSAct对携带两种不同黑色素瘤的小鼠有很强的治疗反应。从这项工作中出现的概念和新的治疗方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视野。具体地说，虽然几乎所有的癌症治疗方法都依赖于小分子化疗药物或单抗，但拟议的工作引入了一种全新的一流治疗性蛋白质。此外，由于TrpRSAct的作用机制不同于已批准的化疗药物或单抗，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联合使用时具有很强的活性。这一结合的成功无疑是因为TrpRSAct的作用机制不同。因此，除了单独使用外，TrpRSAct还可能导致许多新的和扩大的联合疗法。 公共卫生相关性：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。

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. PUBLIC HEALTH RELEVANCE: This project focuses on the establishment of a new class of natural proteins as therapeutics for treatment of cancers.