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

描述(申请人提供)：我们提议的研究将确定通过RNA结合蛋白(RBPs)改变口腔粘膜炎发生和进展的转录后调控，RBPs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、免疫触发和发育线索。HUR编码许多炎症和凋亡相关的mRNAs，包括我们打算研究的下游靶点的细胞因子、白介素类和促凋亡因子。鉴于HUR对这些关键调节因子表达的影响，我们对HUR蛋白结合mRNAs以及它们在化疗和放射治疗中是如何调节的很感兴趣。因此，我们的总体目标是破译HUR蛋白在化疗-放射治疗期间如何影响口腔粘膜炎基因的表达。其次，口腔粘膜炎启动了HUR的翻译后修饰，而HUR又通过mRNA的稳定性促进炎症和细胞凋亡。有趣的是，HUR在化疗中经历了裂解修饰；因此，我们试图了解化疗期间HUR裂解是否在HUR与mRNAs的关联中起重要作用。最后，我们将测试HUR的过表达是否通过mRNA转换途径抑制炎症和细胞凋亡，从而保护口腔粘膜炎。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，并将为未来对HUR相关口腔疾病的研究提供关键。

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.