Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis

RNA结合蛋白介导的口腔粘膜炎细胞凋亡机制

基本信息

批准号：
8993725
负责人：
Viswanathan Palanisamy
金额：
$ 2.53万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8993725
关键词：
3&apos Untranslated Regions Adverse effects Affect Apoptosis Apoptotic BAX gene Binding Caspase Cell Death Cell Survival Cells Cellular biology Cues Cultured Cells Cytoplasm Data Development Dominant-Negative Mutation Elements Epithelial Epithelial Cells Etiology Eukaryotic Cell Event Foundations Future Gene Delivery Gene Expression Gene Expression Regulation Genes Genetic Translation Goals Growth Health HuR protein Human Immune Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukins Ionizing radiation Lead Mediating Messenger RNA Metabolism Methods Modeling Modification Molecular Molecular Profiling Mouth Diseases Mucositis Mus Nuclear Oral Oral mucous membrane structure PTGS2 gene Pain Pathway interactions Post-Transcriptional Regulation Post-Translational Protein Processing Process Protein Binding Protein Isoforms Proteins RNA RNA-Binding Proteins Radiation Radiation therapy Regulator Genes Reporting Research Role Signal Transduction Stress System TNF gene TNFRSF1A gene Testing Tongue Transcript Translations Vision Work adenoviral-mediated base cancer therapy chemoradiation chemotherapy cytokine in vivo mRNA Decay mRNA Expression mRNA Stability mouse model novel oral mucositis overexpression response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Our proposed research will determine the post-transcriptional regulation that changes oral mucositis development and progression via RNA binding proteins (RBPs), which are critical regulators of gene expression in most eukaryotic cells. These proteins influence key aspects of mRNA metabolism including nuclear transit and cytoplasmic export, transport, storage, translation, and turnover. First, among various RNA- binding proteins, HuR is a prominent protein influencing cellular response to stress, proliferative signals, immune triggers, and developmental cues. HuR encodes many inflammation and apoptosis-related mRNAs including cytokines, interleukins and pro-apoptotic factors which are downstream targets we intend to study. Given HuR's influence on expression of these key modulators, we are intrigued about HuR protein binding mRNAs and how they are regulated under chemo-radiotherapy. Hence, our overall goal is to decipher how protein HuR influences oral mucositis gene expression during chemo-radiotherapy. Second, oral mucositis initiates post-translational modification of HuR which in turn, promotes inflammation and apoptosis through mRNA stability. Interestingly, HuR undergoes cleavage modifications under chemotherapy; hence, we seek to understand whether HuR cleavage during chemotherapy is important in HuR association with mRNAs. Finally, we will test whether overexpression of HuR protect oral mucositis through repressing inflammation and apoptosis through mRNA turnover pathway. Thus, our data will provide a foundation for understanding the role of HuR in oral mucositis-associated gene regulation and will be pivotal for future studies into HuR-associated oral diseases.

描述（由申请人提供）：我们提出的研究将确定通过 RNA 结合蛋白 (RBP) 改变口腔粘膜炎发生和进展的转录后调节，RBP 是大多数真核细胞中基因表达的关键调节因子。这些蛋白质影响 mRNA 代谢的关键方面，包括核转运和细胞质输出、运输、储存、翻译和周转。首先，在各种 RNA 结合蛋白中，HuR 是影响细胞对应激、增殖反应的重要蛋白。信号、免疫触发因素和发育线索。 HuR 编码许多炎症和凋亡相关的 mRNA，包括细胞因子、白细胞介素和促凋亡因子，这些都是我们打算研究的下游靶点。鉴于 HuR 对这些关键调节剂表达的影响，我们对 HuR 蛋白结合 mRNA 以及它们在放化疗下的调节方式很感兴趣。因此，我们的总体目标是破译HuR蛋白在放化疗期间如何影响口腔粘膜炎基因表达。其次，口腔粘膜炎启动 HuR 的翻译后修饰，进而通过 mRNA 稳定性促进炎症和细胞凋亡。有趣的是，HuR 在化疗过程中发生了裂解修饰；因此，我们试图了解化疗期间 HuR 裂解对于 HuR 与 mRNA 的关联是否重要。最后，我们将测试 HuR 的过度表达是否通过 mRNA 周转途径抑制炎症和细胞凋亡来保护口腔粘膜炎。因此，我们的数据将为理解 HuR 在口腔粘膜炎相关基因调控中的作用提供基础，并将对于未来 HuR 相关口腔疾病的研究至关重要。