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（信号换能器和转录3）是转录调节器，起着至关重要的作用在细胞的恶性转化中，肿瘤生长和转移。 STAT3活动或表达是在70％的人类肿瘤中上调，导致快速癌症的进展，因此这是一种潜力癌症治疗中的药理学靶标。已经证明STAT3敲低降低了异常细胞生长。但是，STAT3活性的直接和间接抑制剂没有提供预期功效，要求寻找STAT3抑制的替代策略。 Stat3异常表达的存在在不同类型的肿瘤和通过降低STAT3表达治疗癌症的潜在能力中确定研究的重要性。当前项目的核心思想是基于对STAT3的控制通过调制新途径的组件，其在核糖体上的合成过程中的表达最近被我们发现。专门的RAPP（调节异常蛋白质产生）途径调节蛋白质的合成，降解在其期间未正确相互作用的蛋白质的mRNA 核糖体上的合成。我们的假设是Rapp Translatitation Conulators可以用来控制STAT3表达，因此限制了细胞增殖和肿瘤生长。这个概念 STAT3法规的类型以前从未探索过，对STAT3转化伙伴和关于它们控制STAT3表达的调制，从而证明了项目的新颖性。我们的初步数据表明，RAPP途径与STAT3的调节有关。以下具体目的是为该项目设计：（1）在核糖体的合成过程中确定新型STAT3转化伙伴，（2）检验以下假设，即可以调制RAPP翻译调节器以减少STAT3 表达和癌细胞增殖。该研究基于独特的检测技术和通过特定于网站的照片 - 跨链接和IPINCH方法在翻译过程中识别蛋白质。我们将使用候选和公正的方法在STAT3控制中测试RAPP调节器。实验也将涉及细胞培养模型和RNA干扰技术或过量生产以验证参与 STAT3法规中的RAPP组件。在这个项目中，我们将确定该项目的潜在抗癌特性通过测量癌细胞增殖和凋亡来调节RAPP。提案的成功将建立通过动物模型和使用化学调节剂（潜在药物）的未来研究的基础开发新的抗癌医学。可能，该建议将导致概念上的新发展癌症药理治疗方向。