Development of an Anti-Cancer Approach Through a Novel Pathway of Translational Regulation

通过转化调控的新途径开发抗癌方法

基本信息

批准号：
10727837
负责人：
Andrey L Karamyshev
金额：
$ 15.3万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727837
关键词：
Abnormal Cell Animal Model Apoptosis Bioinformatics Cancer Cell Growth Cause of Death Cell Culture Techniques Cell Line Cell Proliferation Cells Cessation of life Chemicals Data Defect Detection Development Drug Targeting Enzymes Failure Foundations Future Genetic Genetic Transcription Health Heat-Shock Proteins 70 Human Immunofluorescence Immunologic In Vitro Malignant - descriptor Malignant Neoplasms Measures Mediating Medicine Messenger RNA Modeling Modification Molecular Molecular Chaperones Neoplasm Metastasis Normal Cell Pathway interactions Persons Pharmaceutical Preparations Pharmacological Treatment Pilot Projects Play Positioning Attribute Production Prognosis Property Protein Biosynthesis Proteins Quality Control RNA Interference Recording of previous events Regulation Ribosomes Role Set protein Signaling Protein Site Small Interfering RNA Societies Stat3 protein System Techniques Technology Testing Time Toxic effect Transfer RNA Translational Regulation Translations United States Western Blotting anti-cancer anticancer treatment cancer care cancer cell cancer diagnosis cancer therapy cancer type cell growth cell transformation chaperonin clinical application cost design experimental study inhibitor knock-down mRNA Expression mRNA Transcript Degradation novel novel therapeutic intervention overexpression pharmacologic polypeptide prefoldin protein expression success targeted treatment tool tumor tumor growth tumor progression uncontrolled cell growth

项目摘要

ABSTRACT STAT3 (Signal Transducer and Activator of Transcription 3) is a transcriptional regulator that plays crucial role in malignant transformation of the cells, tumor growth and metastasis. STAT3 activity or expression is upregulated in 70% of human tumors contributing to a rapid cancer progression and therefore it is a potential pharmacological target in cancer treatments. It was demonstrated that STAT3 knockdown reduced abnormal cell growth. However, direct and indirect inhibitors of STAT3 activity did not provide expected efficacy, demanding search for alternative strategies for STAT3 inhibition. The presence of STAT3 aberrant expression in different types of tumors and potential ability to treat cancer through decrease of STAT3 expression determines high significance of the study. The central idea of the current project is based on control of STAT3 expression during its synthesis on the ribosome through modulation of components of the novel pathway recently discovered by us. The RAPP (Regulation of Aberrant Protein Production) pathway specifically regulates protein synthesis, degrading mRNAs of the proteins that do not properly interact during their synthesis on the ribosome. Our hypothesis is that the RAPP translational regulators may be used to control STAT3 expression and therefore restrict cell proliferation and tumor growth. The concept of this type of STAT3 regulation was never explored before, little is known about STAT3 translational partners and about their modulation to control STAT3 expression, thus demonstrating novelty of the project. Our preliminary data demonstrate that the RAPP pathway is involved in regulation of STAT3. The following specific aims are designed for this project: (1) identify novel STAT3 translational partners during its synthesis on the ribosome, and (2) test the hypothesis that RAPP translational regulators can be modulated to decrease STAT3 expression and cancer cell proliferation. The study is based on unique technologies for detection and identification of proteins during translation by site-specific photo-crosslinking and iPINCH approaches. We will use candidate and unbiased approaches to test RAPP regulators in STAT3 control. The experiments will also involve cell culture models and RNA interference techniques or overproduction to verify involvement of the RAPP components in STAT3 regulation. In this project we will determine potential anti-cancer properties of the RAPP modulation by measuring cancer cell proliferation and apoptosis. The success of the proposal will build a foundation for the future studies with animal models and use of chemical regulators (potential drugs) to develop new anti-cancer medicine. Potentially, this proposal will lead to development of conceptually new directions in pharmacological treatments of cancer.

抽象的 STAT3（转录信号转导和激活因子 3）是一种转录调节因子，发挥着至关重要的作用细胞恶性转化、肿瘤生长和转移。 STAT3 活性或表达是 70% 的人类肿瘤中表达上调，导致癌症快速进展，因此它是一种潜在的癌症治疗中的药理学目标。研究表明，STAT3 敲低可减少异常细胞生长。然而，STAT3活性的直接和间接抑制剂并没有提供预期的功效，迫切需要寻找 STAT3 抑制的替代策略。 STAT3 异常表达的存在在不同类型的肿瘤中的作用以及通过降低 STAT3 表达来治疗癌症的潜在能力决定了该研究的高度意义。当前项目的中心思想是基于STAT3的控制通过调节新途径的成分在核糖体上合成过程中表达最近被我们发现。 RAPP（异常蛋白质生产调节）途径调节蛋白质合成，降解在其作用过程中不能正确相互作用的蛋白质的 mRNA 在核糖体上合成。我们的假设是 RAPP 翻译调节因子可用于控制 STAT3 表达，从而限制细胞增殖和肿瘤生长。这个的概念之前从未探索过 STAT3 调控的类型，对 STAT3 翻译伙伴知之甚少，关于它们控制 STAT3 表达的调节，从而证明了该项目的新颖性。我们的初步数据表明 RAPP 通路参与 STAT3 的调节。具体目标如下为本项目设计：(1) 在核糖体上合成过程中识别新的 STAT3 翻译伙伴， (2) 检验 RAPP 翻译调节因子可以被调节以减少 STAT3 的假设表达和癌细胞增殖。该研究基于独特的检测技术和通过位点特异性光交联和 iPINCH 方法识别翻译过程中的蛋白质。我们将使用候选和公正的方法来测试 STAT3 控制中的 RAPP 调节器。实验还将涉及细胞培养模型和 RNA 干扰技术或过量生产，以验证 STAT3 调节中的 RAPP 组件。在这个项目中，我们将确定潜在的抗癌特性通过测量癌细胞增殖和凋亡来调节 RAPP。该提案的成功将建立为未来的动物模型研究和使用化学调节剂（潜在药物）奠定基础开发新的抗癌药物。该提案有可能导致新概念的开发癌症药物治疗的方向。